Compounds for kinase modulation, and indications therefor

ABSTRACT

Compounds active on protein kinases and methods for regulating protein kinase pathways are described, as well as methods of using such compounds to treat diseases and conditions associated with aberrant activity of protein kinases.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit under 35 U.S.C. § 119(e) to U.S.Provisional Application No. 61/829,190, filed on May 30, 2013, theentirety of which is incorporated herein by reference.

FIELD

The present disclosure relates to kinase inhibitors which selectivelymodulate kinases, and uses therefor. Particular embodiments contemplatedisease indications which are amenable to treatment by modulation ofkinase activity.

BACKGROUND

Receptor protein kinases regulate key signal transduction cascades thatcontrol or are involved in the control of a plethora of physiologicalfunctions including cellular growth and proliferation, celldifferentiation, cellular development, cell division, cell adhesion,stress response, short-range contact-mediated axonal guidance,transcription regulation, aberrant mitogenesis, angiogenesis, abnormalendothelial cell-cell or cell-matrix interactions during vasculardevelopment, inflammation, lymphohematopoietic stem cell activity,protective immunity against specific bacteria, allergic asthma, aberranttissue-specific responses to the activation of the JNK signaltransduction pathway, cell transformation, memory, apoptosis,competitive activity-dependent synapse modification at the neuromuscularsynapse, immunological mediation of disease, and calcium regulation.

Exemplary disease states associated with aberrant regulation of proteinkinases include, for example without limitation, acrocephalo-syndactylytype I, acute myeloid leukemia, AIDS-induced non-Hodgkin's lymphoma,Alzheimer's disease, amyotrophic lateral sclerosis, arthritis, asthma,atherosclerosis, atopic dermatitis, autoimmune diseases, bacterialinfection, bladder cancer, cancer of the breast, cancer of the centralnervous system, cancer of the colon, cancer of the endometrium, cancerof the fallopian tube, cancer of the gastrointestinal tract, cancer ofthe ovary, heart failure, chronic myeloid leukemia, colon carcinoma,colorectal cancer, chronic obstructive pulmonary disease (COPD), CrouzonSyndrome, diabetes, diabetic nephropathy, emphysema, endometriosis,epidermoid cancer, fibrotic disorders, gastrointestinal stromal tumor(GIST), glomerulonephritis, Graves' disease, head injury, hepatocellularcarcinoma, Hirschsprung's disease, human gliomas, immunodeficiencydiseases, inflammatory disorders, ischemic stroke, Jackson-Weisssyndrome, leiomyosarcoma, leukemias, lupus nephritis, malignantmelanoma, malignant nephrosclerosis, mastocytosis, mast cell tumors,melanoma of the colon, MEN2 syndromes, metabolic disorders, migraine,multiple sclerosis, myeloproliferative disorders, nephritis,neurodegenerative diseases, neurotraumatic diseases, lung cancer, nonsmall cell lung cancer, organ transplant rejection, osteoporosis, pain,Parkinson's disease, Pfeiffer Syndrome, polycystic kidney disease,primary lymphoedema, prostate cancer, psoriasis, vascular restenosis,rheumatoid arthritis, dermal and tissue scarring, selective T-celldefect (STD), severe combined immunodeficiency (SCID), small cell lungcancer, spinal cord injury, squamous cell carcinoma, systemic lupuserythematosis, testicular cancer, thrombotic microangiopathy syndromes,Wegener's granulomatosis, X-linked agammaglobulinemia, viral infection,diabetic retinopathy, alopecia, erectile dysfunction, maculardegeneration, chronic lymphocytic leukemia (CLL), myelodysplasticsyndrome (MDS), neurofibromatosis, and tuberous sclerosis.

The identification of activating BRAF mutations (primarily missensesubstitutions for Valine-600 or BRAF^(V600) in cancer supports afunctionally important role for BRAF in the pathogenesis of thesemalignancies (Davies, H. et al. Nature 417, 949-954 (2002)). SpecificBRAF inhibitors including vemurafenib and dabrafenib have demonstratedboth objective tumor response and, in the case of vemurafenib, overallsurvival benefit in mutant BRAF^(V600) driven melanoma (Flaherty, K. T.et al. N Engl J Med 363, 809-819 (2010); Chapman, P. B. et al. N Engl JMed 364, 2507-2516 (2011); Sosman, J. A. et al. N Engl J Med 366,707-714 (2012); Hauschild, A. et al. Lancet 380, 358-365 (2012); Bollag,G. et al. Nature 467, 596-599 (2010); and Stellwagen, J. C. et al.Bioorg Med Chem Lett 21, 4436-4440 (2011)). The clinical effectivenessof BRAF inhibitor-based therapy depends on complete abolition of theMAPK pathway output in tumors harboring BRAF mutations (Bollag, G. etal. Nature 467, 596-599 (2010)). However these compounds paradoxicallyactivate the MAPK pathway in cells bearing oncogenic RAS or elevatedupstream receptor signaling (Hatzivassiliou, G. et al. Nature 464,431-435 (2010); Heidorn, S. J. et al. Cell 140, 209-221 (2010); andPoulikakos, P. I., Zhang, C., Bollag, G., Shokat, K. M. & Rosen, N.Nature 464, 427-430 (2010)). This activation can lead to cellularproliferation and has been associated clinically with appearance ofcutaneous squamous cell carcinomas (cuSCC) and keratoacanthomas (KAs),sometimes within weeks of initiation of therapy (Hauschild, A. et al.Lancet 380, 358-365 (2012); Bollag, G. et al. Nature 467, 596-599(2010); Huang, V., Hepper, D., Anadkat, M. & Cornelius, L. Arch Dermatol148, 628-633 (2012); and Anforth, R. M. et al. Br J Dermatol 167,1153-1160 (2012)). Accordingly, there is a need in the art for compoundsand methods of use thereof for modulation of receptor protein kinases.The disclosure herein meets this and other needs.

SUMMARY

In one aspect, provided herewith is a compound having formula (I′):

or a pharmaceutically acceptable salt, a prodrug, a solvate, a tautomeror an isomer thereof,

Y is —N(R¹)(R²) or —C(R⁸)(R⁹)(R¹⁰);

R¹ and R² are each independently optionally substituted alkyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted cycloalkyl; or R¹ and R² are taken together toform an optionally substituted 4-, 5- or 6-membered heterocycloalkylring having from 0-1 additional heteroatoms selected from O, N or S;

R⁸, R⁹ and R¹⁰ are each independently H, optionally substituted C₁₋₆alkyl, optionally substituted C₁₋₆ haloalkyl, optionally substitutedC₁₋₆ haloalkoxy, optionally substituted C₃₋₈ cycloalkyl, optionallysubstituted aryl, optionally substituted heterocycloalkyl, optionallysubstituted heteroaryl; or any of two of the R⁸, R⁹ and R¹⁰ groups takentogether with the carbon atom to which they are attached form a 3 to8-membered optionally substituted non-aromatic ring having from 0 to 2heteroatoms as ring members selected from N, O or S; provided at eachoccurrence, at least two of the R⁸, R⁹ and R¹⁰ groups are notsimultaneously hydrogen;

R³ is H or C₁₋₆alkyl;

L¹ and L² are each independently a bond, —C(O)—, —C(S)—, —C(O)NH—,—NHC(O)— or optionally substituted —C(═CH₂)—, wherein two substituentsattached to the same methylene carbon in the —C(═CH₂)— group areoptionally taken together to form an optionally substituted 5- or6-membered ring having from 0-4 heteroatoms selected from O, N or S,where N and S are optionally oxidized; E is an optionally substitutedaryl or optionally substituted 5- or 6-membered heteroaryl; Z is anoptionally substituted aryl or optionally substituted heteroaryl, whenL² is a bond and E is

then Z is other than a 5-position optionally substituted

core, and wherein the wavy line in

indicates the attachment to the rest of the molecule, wherein the singlewavy line in

indicates the attachment to —N(R³)SO₂Y group and the double wavy lineindicates the attachment to E and wherein R⁴ is H or F.

In some embodiments, provided herewith is a compound of formula (I):

or a pharmaceutically acceptable salt, a prodrug, a solvate, a tautomeror an isomer thereof,

Y is —N(R¹)(R²) or —C(R⁸)(R⁹)(R¹⁰);

R¹ and R² are each independently optionally substituted alkyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted cycloalkyl; or R¹ and R² taken together with thenitrogen to which they attach form an optionally substituted 5- or6-membered heterocycloalkyl ring having from 0-1 additional heteroatomsas ring members selected from O, N or S;

R⁸, R⁹ and R¹⁰ are each independently H, optionally substituted C₁₋₆alkyl, optionally substituted C₁₋₆ haloalkyl, optionally substitutedC₁₋₆ haloalkoxy, optionally substituted C₃₋₈ cycloalkyl, optionallysubstituted aryl, optionally substituted heterocycloalkyl, optionallysubstituted heteroaryl; or any of two of the R⁸, R⁹ and R¹⁰ groups takentogether with the carbon atom to which they are attached form a 3 to8-membered optionally substituted non-aromatic ring having from 0 to 2heteroatoms as ring members selected from N, O or S; provided at eachoccurrence, at least two of the R⁸, R⁹ and R¹⁰ groups are notsimultaneously hydrogen;

R³ is H or C₁₋₆alkyl;

R⁴ is halogen, hydrogen, C₁₋₂alkyl, C₁₋₂haloalkyl, CN, C₁₋₂haloalkoxy orC₁₋₂alkoxy;

L is a bond, —C(O)—, —C(S)—, —C(O)NH—, —NHC(O)— or optionallysubstituted —C(═CH₂)—, wherein two substituents attached to the samemethylene carbon in the —C(═CH₂)— group are optionally taken together toform an optionally substituted 5- or 6-membered ring having from 0-4heteroatoms selected from O, N or S, where N and S are optionallyoxidized;

Z is an optionally substituted aryl or optionally substitutedheteroaryl, provided that Z is other than an optionally substituted

core when R⁴ is attached at the ortho position with respect to the -L-Zsubstituent on the phenyl ring, wherein the wavy line indicates thepoint of attachment to the rest of the molecule; and provided that thecompound is not4-[[(1S)-1-cyclopropylethyl]amino]-5-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-7H-pyrrolo[2,3-d]pyrimidineor4-[[(1R)-1-cyclopropylethyl]amino]-5-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-7H-pyrrolo[2,3-d]pyrimidine.

In another aspect, provided herewith is a method for regulating ormodulating a MAPK pathway signaling. The method includes selectivelyinhibiting a mutant RAF kinase, wherein the inhibition of mutant kinasedoes not cause or induce the activation of pERK and expression ofupstream EGFR ligands. In some embodiments, the mutant RAF kinase is amutant BRAF kinase. In certain embodiments, the method includes the useof a compound as described herein in regulating or modulating a MAPKpathway signaling.

In another aspect, provided herewith is a composition. The compositionincludes a compound having a sulfamoylamino moiety, a compound offormula (I) or (I′), or any sub-generic formulas of formula (I), acompound as recited in any of the claims and described herein or apharmaceutically acceptable salt or solvate thereof, and apharmaceutically acceptable excipient or carrier. The disclosure alsoprovides a composition, which includes a compound as recited in theclaims and described herein, a pharmaceutically acceptable excipient orcarrier, and another therapeutic agent.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Paradox Breakers, e.g. compounds containing —N(R³)S(O)₂Y moietydissociate MAPK pathway inhibition from the opposing pathway activationproperty. (a) pERK IC₅₀ curves in the A375 (BRAF^(V600E)) cell line andpERK EC₅₀ curves in the B9 (HRAS^(Q61L)) and IPC-298 (NRAS^(Q61L)) celllines. For EC₅₀, the data were normalized to the pERK level induced by10 μM compound P-1000 (set as 100%). (b) Immunoblot analysis of pERK inhuman SCC cell line A431 and human breast carcinoma cell line SKBR3treated by vemurafenib or a compound of formula (I), e.g. compound A.(c) Compound A and vemurafenib treatments inhibited the growth ofCOLO205 human colorectal cancer xenografts. (d) B9 cells displayedincreased anchorage independent cell growth in the presence ofincreasing concentrations of vemurafenib and compound P-1000 whereas acompound of formula (I), e.g. compound A had no effect. (e) B9subcutaneous xenografts were stimulated by vemurafenib administered at50 mg/kg, but not by compound A at the same dose (and exposure).

FIG. 2. A link between EGFR signaling and vemurafenib-induced cuSCC. (a)Hierarchical clustering of the 239 Affymetrix gene probes (see Table 4for a complete list) that showed altered expression in B9 cells inresponse to either vemurafenib (233 probes) or a compound of formula(I), e.g. compound A (4 probes) treatment. The single overlap, Cyp1b1,and four representative MAPK pathway-responsive genes as well as threegenes that encode EGFR ligands are marked. The inset shows the foldchange in the expression of four EGFR ligands along with EGFR itself.(b) vemurafenib, but not compound A, induced TGFα protein expression inB9 cells. (c) Exogenous TGFα stimulated the anchorage-independent growthof B9 cells. (d) Erlotinib inhibited vemurafenib-induced growth of B9cells.

FIG. 3. Illustration of the differentiating molecular mechanism ofParadox Breakers, e.g. compounds containing a sulfamoylamino moiety orcompounds of formula (I′) or (I). (a) Comparative binding of theN-ethylmethyl-sulfamoid tail in compound A (with carbon atoms in green)and that of the propyl-sulfonamide tail of vemurafenib (with carbonatoms in cyan). The complexes are viewed from the dimer interfaces. TheN-lobe is removed to show the inhibitor and its interaction with thefour-residue R-spine (Leu505, Ile527, Leu567 and Phe595) and αC helix(orange). A dotted surface around the N-methyl group in compound Aillustrates its close contact with the R-spine residue Leu505. Phe595 ofthe DFG motif is depicted as spheres to indicate the DFG-in conformationof the activation loop (Type 1 binding mode). Other pocket residues arerendered in sticks; (b) BRAF-CRAF heterodimers in B9 and IPC-298 cellsafter one hour treatment with increasing concentrations of compound A orvemurafenib, (c) pMEK and growth IC50 curves for vemurafenib andcompound A in the SKMEL-239 parental cell line and a representativevemurafenib-resistant clone (C3) that expresses a spliced variant ofBRAF^(V600E). Vemurafenib-resistant cells remain relatively sensitive toParadox Breakers.

FIG. 4. The structural determinant of Paradox Breakers, theN-ethylmethyl-sulfamoyl group, can be transferred to another chemicalseries to drastically change its biological profile. Dabrafenib, ahighly potent inhibitor of pERK in BRAF^(V600E) cell lines, exhibited anunusual bell-shaped pERK activation curve in mutant NRAS cell lines (B9and IPC-298). Substituting the 2,6-difluoro-phenylsulfonamide withN-ethylmethylsulfamoid resulted in a compound (P-0352) that showsmarkedly reduced pERK activation in mutant RAS cells with only amoderate decrease in pERK IC₅₀ in BRAF^(V600E) cell line (A375).

FIG. 5. Compounds containing sulfamoylamino moiety, for example,compounds of formula (I), such as compound A, and vemurafenib showsimilar potency in blocking pERK signaling in (a) human BRAF^(V600E)melanoma cell COLO829 but in (b) RAS activated human colorectalcarcinoma cell line HCT116 (KRAS^(G13D)), (c) EGFR-overexpressed humanSCC cell line A431 or (d) HER2-overexpressed human breast carcinoma cellline SKBR3, vemurafenib paradoxically activates MAPK signaling whereascompound A causes negligible pERK increase. The pERK curves in COLO829and HCT116 were generated using AlphaScreen® assay. (c) and (d)Quantification of the immunoblots in FIG. 1 c.

FIG. 6. Vemurafenib significantly induces the expression of EGFR ligandsin transformed keratinocytes. (a) vemurafenib's upregulation of AREGprotein in B9 cell supernatant and (b) its upregulation of HB-EGF in B9cell lysates were confirmed by ELISA assay. Compounds containingsulfamoylamino moiety, for example, compounds of formula (I), don'tinduce the expression of EGFR ligands. (c) and (d) Exogenous EGFRligands AREG and HB-EGF recapitulate the growth stimulating effect ofvemurafenib.

FIG. 7. Modulation of RAF dimerization by RAF inhibitors. (a)Immunoblots of lysates detecting endogenous BRAF-CRAF heterodimer Withthe exception of Paradox Breaker, for example, e.g. compounds containinga sulfamoylamino moiety or compounds of formula (I), all known RAFinhibitors induce BRAF-CRAF dimer formation. (b) Biochemicaldimerization assays using recombinant kinase domains show that acompound of formula (I), e.g. compound A interrupts the formation ofBRAF-CRAF heterodimer and CRAF homodimer.

DETAILED DESCRIPTION I. Definitions

As used herein the following definitions apply unless clearly indicatedotherwise:

It is noted here that as used in this specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referenceunless the context clearly dictates otherwise.

“Halogen” or “halo” refers to all halogens, that is, chloro (Cl), fluoro(F), bromo (Br), or iodo (I).

“Hydroxyl” or “hydroxy” refers to the group —OH.

“Thiol” refers to the group —SH.

The term “alkyl”, by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain hydrocarbon,having the number of carbon atoms designated (i.e. C₁₋₆ means one to sixcarbons). Representative alkyl groups include straight and branchedchain alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbonatoms. Further representative alkyl groups include straight and branchedchain alkyl groups having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms.Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl,n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl,n-octyl, and the like. For each of the definitions herein (e.g., alkyl,alkoxy, alkylamino, alkylthio, alkylene, haloalkyl, arylalkyl,cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl), when a prefixis not included to indicate the number of carbon atoms in an alkylportion, the alkyl moiety or portion thereof will have 12 or fewer mainchain carbon atoms or 8 or fewer main chain carbon atoms or 6 or fewermain chain carbon atoms. For example, C₁₋₆ alkyl refers to a straight orbranched hydrocarbon having 1, 2, 3, 4, 5 or 6 carbon atoms andincludes, but is not limited to, C₁₋₂ alkyl, C₁₋₄ alkyl, C₂₋₆ alkyl,C₂₋₄ alkyl, C₁₋₆ alkyl, C₂₋₈ alkyl, C₁₋₇ alkyl, C₂₋₇ alkyl and C₃₋₆alkyl. “Fluoro substituted alkyl” denotes an alkyl group substitutedwith one or more fluoro atoms, such as perfluoroalkyl, where preferablythe lower alkyl is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also1, 2, or 3 fluoro atoms. While it is understood that substitutions areattached at any available atom to produce a stable compound, whenoptionally substituted alkyl is an R group of a moiety such as —OR (e.g.alkoxy), —SR (e.g. thioalkyl), —NHR (e.g. alkylamino), —C(O)NHR, and thelike, substitution of the alkyl R group is such that substitution of thealkyl carbon bound to any O, S, or N of the moiety (except where N is aheteroaryl ring atom) excludes substituents that would result in any O,S, or N of the substituent (except where N is a heteroaryl ring atom)being bound to the alkyl carbon bound to any O, S, or N of the moiety.As used herein, “deuterated C₁₋₆alkyl” is meant to include partiallydeuterated or perdeuterated C₁₋₆alkyl groups. Non-limiting examplesinclude —CD₃, CD₃CH₂—, CD₃CD₂-, —CD(CD₃)₂, —CD(CH₃)₂, and the like.

The term “alkylene” by itself or as part of another substituent means alinear or branched saturated divalent hydrocarbon moiety derived from analkane having the number of carbon atoms indicated in the prefix. Forexample, (i.e., C₁₋₆ means one to six carbons; C₁₋₆ alkylene is meant toinclude methylene, ethylene, propylene, 2-methylpropylene, pentylene,hexylene and the like). C₁₋₄ alkylene includes methylene —CH₂—, ethylene—CH₂CH₂—, propylene —CH₂CH₂CH₂—, and isopropylene —CH(CH₃)CH₂—,—CH₂CH(CH₃)—, —CH₂—(CH₂)₂CH₂—, —CH₂—CH(CH₃)CH₂—, —CH₂—C(CH₃)₂,—CH₂—CH₂CH(CH₃)—. Typically, an alkyl (or alkylene) group will have from1 to 24 carbon atoms, with those groups having 10 or fewer, 8 or fewer,or 6 or fewer carbon atoms being preferred in the present disclosure.When a prefix is not included to indicate the number of carbon atoms inan alkylene portion, the alkylene moiety or portion thereof will have 12or fewer main chain carbon atoms or 8 or fewer main chain carbon atoms,6 or fewer main chain carbon atoms or 4 or fewer main chain carbonatoms.

The term “alkenylene” means a linear bivalent hydrocarbon radical or abranched divalent hydrocarbon radical having the number of carbon atomsindicated in the prefix and containing at least one double bond. Forexample, i.e., C₂₋₆ means two to six carbons; C₂₋₆ alkenylene is meantto include, but is not limited to, —CH═CH—, —CH₂—CH═CH—,—CH₂—CH═C(CH₃)—, —CH═CH—CH═CH—, and the like. Similarly, the term“alkynylene” refers to a linear bivalent hydrocarbon radical or abranched divalent hydrocarbon radical containing at least one triplebond and having the number of carbon atoms indicated in the prefix. Forexample, C₂₋₆ means two to six carbons; C₂₋₆ alkynlene is meant toinclude, but is not limited to, —C≡C—, —C≡CCH₂—, —CH₂—C≡CCH₂—,—C≡CCH(CH₃)—, and the like. When a prefix is not included to indicatethe number of carbon atoms in an alkenylene or alkynlene portion, thealkenylene moiety or portion thereof will have 12 or fewer main chaincarbon atoms, or 8 or fewer main chain carbon atoms, or 6 or fewer mainchain carbon atoms, or 4 or fewer main chain carbon atoms.

“Cycloalkyl”, “Carbocyclic” or “Carbocycle” by itself or as part ofanother substituent, means saturated or unsaturated, non-aromaticmonocyclic, bicyclic or tricyclic carbon ring systems having the numberof carbon atoms indicated in the prefix or if unspecified having 3-10,also 3-8, more preferably 3-6, ring members per ring, such ascyclopropyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, adamantyl, and thelike, where one or two ring carbon atoms may optionally be replaced by acarbonyl. Cycloalkyl refers to hydrocarbon rings having the indicatednumber of ring atoms (e.g., C₃₋₈ cycloalkyl means three to eight ringcarbon atoms). “Cycloalkyl” or “carbocycle” refers to a mono-bicyclic orpolycyclic group such as, for example, bicyclo[2.2.1]heptane,bicyclo[2.2.2]octane, etc. When used in connection with cycloalkylsubstituents, the term “polycyclic” refers herein to fused and non-fusedalkyl cyclic structures. “Cycloalkyl” or “carbocycle” may form a bridgedring or a spiro ring. The cycloalkyl group may have one or more ringdouble or triple bond(s).

“Cycloalkylalkyl” means an -(alkylene)-cycloalkyl group where alkyleneas defined herein has the indicated number of carbon atoms or ifunspecified having six or fewer, preferably four or fewer main chaincarbon atoms; and cycloalkyl is as defined herein has the indicatednumber of carbon atoms or if unspecified having 3-10, also 3-8, morepreferably 3-6, ring members per ring. C₃₋₈cycloalkyl-C₁₋₂alkyl is meantto have 3 to 8 ring carbon atoms and 1 to 2 alkylene chain carbon atoms.Exemplary cycloalkylalkyl includes, e.g., cyclopropylmethylene,cyclobutylethylene, cyclobutylmethylene, and the like.

“Haloalkyl,” is meant to include alkyl substituted by one to sevenhalogen atoms. Haloalkyl includes monohaloalkyl and polyhaloalkyl. Forexample, the term “C₁₋₆ haloalkyl” is meant to include trifluoromethyl,difluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, andthe like.

“Haloalkoxy” means a —O-haloalkyl group, where haloalkyl is as definedherein, e.g., trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy,and the like.

“Alkoxy” means a —O-alkyl group, where alkyl is as defined herein.“Cycloalkoxy” refers to a —O-cycloalkyl group, where cycloalkyl is asdefined herein. “Fluoro substituted alkoxy” denotes alkoxy in which thealkyl is substituted with one or more fluoro atoms, where preferably thealkoxy is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3fluoro atoms. While it is understood that substitutions on alkoxy areattached at any available atom to produce a stable compound,substitution of alkoxy is such that O, S, or N (except where N is aheteroaryl ring atom), are not bound to the alkyl carbon bound to thealkoxy O. Further, where alkoxy is described as a substituent of anothermoiety, the alkoxy oxygen is not bound to a carbon atom that is bound toan O, S, or N of the other moiety (except where N is a heteroaryl ringatom), or to an alkene or alkyne carbon of the other moiety.

“Amino” or “amine” denotes the group —NH₂.

“Alkylamino” means a —NH-alkyl group, where alkyl is as defined herein.Exemplary alkylamino groups include CH₃NH—, ethylamino, and the like.

“Dialkylamino” refers to a —N(alkyl)(alkyl) group, where each alkyl isindependently as defined herein. Exemplary dialkylamino groups includedimethylamino, diethylamino, ethylmethylamino, and the like.

“Cycloalkylamino” denotes the group —NR^(dd)R^(ee), where R^(dd) andR^(ee) combine with the nitrogen to form a 5-7 membered heterocycloalkylring, where the heterocycloalkyl may contain an additional heteroatomwithin the ring, such as O, N, or S, and may also be further substitutedwith alkyl. Alternatively, “cycloalkylamino” refers to a —NH-cycloalkylgroup, where cycloalkyl is as defined herein.

“Alkylthio” refers to —S-alkyl, where alkyl is as defined herein.Exemplary alkylthio groups include CH₃S—, ethylthio, and the like.

“Aryl” by itself or as part of another substituent means a monocyclic,bicyclic or polycyclic polyunsaturated aromatic hydrocarbon radicalcontaining 6 to 14 ring carbon atoms, which can be a single ring ormultiple rings (up to three rings) which are fused together or linkedcovalently. Non-limiting examples of unsubstituted aryl groups includephenyl, 1-naphthyl, 2-naphthyl and 4-biphenyl. Exemplary aryl groups,such as phenyl or naphthyl, may be optionally fused with a cycloalkyl ofpreferably 5-7, more preferably 5-6, ring members.

“Arylalkyl” refers to -(alkylene)-aryl, where the alkylene group is asdefined herein and has the indicated number of carbon atoms, or ifunspecified having six or fewer main chain carbon atoms or four or fewermain chain carbon atoms; and aryl is as defined herein. Examples ofarylalkyl include benzyl, phenethyl, 1-methylbenzyl and the like.

“Heteroaryl” by itself or as part of another substituent refers to amonocyclic aromatic ring radical containing 5 or 6 ring atoms, or abicyclic aromatic radical having 8 to 10 atoms, containing one or more,preferably 1-4, more preferably 1-3, even more preferably 1-2,heteroatoms independently selected from the group consisting of O, S,and N. Heteroaryl is also intended to include oxidized S or N, such assulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. A carbon ornitrogen atom is the point of attachment of the heteroaryl ringstructure such that a stable compound is produced. Examples ofheteroaryl groups include, but are not limited to, pyridinyl,pyridazinyl, pyrazinyl, indolizinyl, benzo[b]thienyl, quinazolinyl,purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, pyrazolyl,oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl,tetrazolyl, imidazolyl, triazolyl, furanyl, benzofuryl, indolyl,triazinyl, quinoxalinyl, cinnolinyl, phthalaziniyl, benzotriazinyl,benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl,isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl,thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridinyl,benzothiazolyl, benzothienyl, quinolyl, isoquinolyl, indazolyl,pteridinyl and thiadiazolyl. “Nitrogen containing heteroaryl” refers toheteroaryl wherein any of the heteroatoms is N. As used herein,“heterocyclic aromatic ring” is meant to be a heteroaryl ring.

“Heteroarylalkyl” refers to -(alkylene)-heteroaryl, where the alkylenegroup is as defined herein and has the indicated number of carbon atoms,or if unspecified having six or fewer main chain carbon atoms or four orfewer main chain carbon atoms; and heteroaryl is as defined herein.Examples of heteroarylalkyl include 2-pyridylmethyl, 2-thiazolylethyl,and the like.

“Heterocycloalkyl” refers to a saturated or unsaturated non-aromaticcycloalkyl group that contains from one to five ring heteroatomsselected from N, O, and S, wherein the nitrogen and sulfur atoms areoptionally oxidized, and the nitrogen atom(s) are optionallyquaternized, the remaining ring atoms being C, where one or two C atomsmay optionally be replaced by a carbonyl. The heterocycloalkyl may be amonocyclic, a bicyclic or a polycyclic ring system of 3 to 12,preferably 4 to 10 ring atoms, more preferably 5 to 8 ring atoms inwhich one to five ring atoms are heteroatoms selected from —N═, —N—,—O—, —S—, —S(O)—, or —S(O)₂— and further wherein one or two ring atomsare optionally replaced by a —C(O)— group. The heterocycloalkyl can alsobe a heterocyclic alkyl ring fused with a cycloalkyl, an aryl or aheteroaryl ring. When multiple rings are present, they can be fusedtogether or linked covalently. Each heterocycle typically contains 1, 2,3, 4 or 5, independently selected heteroatoms. Preferably, these groupscontain 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, 0, 1, 2, 3, 4 or 5nitrogen atoms, 0, 1 or 2 sulfur atoms and 0, 1 or 2 oxygen atoms. Morepreferably, these groups contain 1, 2 or 3 nitrogen atoms, 0-1 sulfuratoms and 0-1 oxygen atoms. Non limiting examples of heterocycloalkylgroups include oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl,imidazolidinyl, pyrazolidinyl, butyrolactam moiety, valerolactam moiety,imidazolidinone moiety, hydantoin, dioxolane moiety, phthalimide moiety,piperidine, 1,4-dioxane moiety, morpholinyl, thiomorpholinyl,thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-oxide, piperazinyl,pyranyl, pyridine moiety, 3-pyrrolinyl, thiopyranyl, pyrone moiety,tetrahydrofuranyl, tetrahydrothiophenyl, quinuclidinyl,1-methylpyridin-2-one moiety, 1-methyl-2-oxo-3-pyridyl,1-methyl-2-oxo-4-pyridyl, 1-methyl-2-oxo-5-pyridyl,1-methyl-2-oxo-6-pyridyl, and the like. A heterocycloalkyl group can beattached to the remainder of the molecule through a ring carbon or aheteroatom. As used herein, the term “heterocycloalkylene” by itself oras part of another substituent, refers to a divalent heterocycloalkyl,where the heterocycloalkyl is as defined herein. Non-limiting examplesof heterocycloalkylene include piperazine-1,4-diyl, piperidine-1,4-diyl,1,2,3,6-tetrahydropyridine-1,4-diyl,1,2,3,6-tetrahydropyridine-1,5-diyl,2,3,6,7-tetrahydro-1H-azepine-1,4-diyl,2,3,6,7-tetrahydro-1H-azepine-1,5-diyl, 2,5-dihydro-1H-pyrrole-1,3-diyl,azabicyclo[3.2.1]octane-3,8-diyl,3,8-diazabicyclo[3.2.1]octane-3,8-diyl,8-azabicyclo[3.2.1]octane-3,8-diyl, 2-azabicyclo[2.2.2]octane-2,5-diyl,2,5-diazabicyclo[2.2.2]octane-2,5-diyl, 3-oxomorpholin-2-yl,3-oxomorpholin-4-yl, 3-oxomorpholin-5-yl, 3-oxomorpholin-6-yl,2-oxopiperazin-3-yl, 2-oxopiperazin-4-yl, 2-oxopiperazin-5-yl,2-oxopiperazin-6-yl, 2-oxopiperazin-7-yl, piperazin-1-oxide-2-yl,piperazin-1-oxide-3-yl, piperazin-1-oxide-4-yl, pyridine-2-one-3-yl,pyridine-2-one-4-yl, pyridine-2-one-5-yl, pyridine-2-one-6-yl,pyridine-2-one-7-yl, piperidinyl, morpholinyl, piperazinyl,isoxazolinyl, pyrazolinyl, imidazolinyl, pyrazol-5-one-3-yl,pyrazol-5-one-4-yl, pyrrolidine-2,5-dione-1-yl,pyrrolidine-2,5-dione-3-yl, pyrrolidine-2,5-dione-4-yl,imidazolidine-2,4-dione-1-yl, imidazolidine-2,4-dione-3-yl,imidazolidine-2,4-dione-5-yl, pyrrolidinyl, tetrahydroquinolinyl,decahydroquinolinyl, tetrahydrobenzooxazepinyl, dihydrodibenzooxepinyl,and the like.

“Heterocycloalkylalkyl” refers to -(alkylene)-heterocycloalkyl, wherethe alkylene group is as defined herein and has the indicated number ofcarbon atoms, or if unspecified having six or fewer main chain carbonatoms or four or fewer main chain carbon atoms; and heterocycloalkyl isas defined herein. Non-limiting examples of heterocycloalkyl include,e.g., 2-pyridylmethyl, 2-thiazolylethyl, pyrrolidin-1-ylmethyl,2-piperidinylmethyl, and the like.

The substituents for alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl,cycloalkylalkyl, alkylene, alkenylene, alkynlene, heterocycloalkyl,heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl include, but arenot limited to, R′, halogen, —OH, —NH₂, —NO₂, —CN, —C(O)OH, —C(S)OH,—C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂,—C(NH)NH₂, —OR′, —SR′, —OC(O)R′, —OC(S)R′, —C(O)R′, —C(S)R′, —C(O)OR,—C(S)OR′, —S(O)R′, —S(O)₂R′, —C(O)NHR′, —C(S)NHR′, —C(O)NR′R′,—C(S)NR′R″, —S(O)₂NHR′, —S(O)₂NR′R″, —C(NH)NHR′, —C(NH)NR′R″, —NHC(O)R′,—NHC(S)R′, —NR″C(O)R′, —NR′C(S) R″, —NHS(O)₂R′, —NR′S(O)₂R″,—NHC(O)NHR′, —NHC(S)NHR′, —NR′C(O)NH₂, —NR′C(S)NH₂, —NR′C(O) NHR″,—NR′C(S)NHR″, —NHC(O)NR′R″, —NHC(S)NR′R″, —NR′C(O)NR″R′″,—NR′″C(S)NR′R″, —NHS(O)₂N HR′, —NR′S(O)₂NH₂, —NR′S(O)₂NHR″,—NHS(O)₂NR′R″, —NR′S(O)₂NR′R′″, —NHR′, and —NR′R″ in a number rangingfrom zero to (2m′+1), where m′ is the total number of carbon atoms insuch group. R′, R″ and R′″ each independently refer to hydrogen, C₁₋₈alkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,aryl substituted with 1-3 halogens, C₁₋₈ alkoxy, haloalkyl, haloalkoxyor C₁₋₈ thioalkoxy groups, or unsubstituted aryl-C₁₋₄ alkyl groups. WhenR′ and R″ are attached to the same nitrogen atom, they can be combinedwith the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring. Forexample, —NR′R″ is meant to include 1-pyrrolidinyl and 4-morpholinyl.R′, R″ and R′″ can be further substituted with R^(a1), halogen, —OH,—NH₂, —NO₂, —CN, —C(O)OH, —C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂,—NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —C(NH)NH₂, —OR^(a1), —SR^(a1),—OC(O)R^(a1), —OC(S)R^(a1), —C(O)R^(a1), —C(S)R^(a1), —C(O) OR^(a1),—C(S)OR^(a1), —S(O)R^(a1), —S(O)₂R^(a1), —C(O)NHR^(a1), —C(S)NHR^(a1),—C(O)NR^(1a)R^(a2), —C(S)NR^(a1)R^(a2), —S(O)₂NHR^(a1),—S(O)₂NR^(a1)R^(a2), —C(NH)NHR^(a1), —C(NH)NR^(a1)R^(a2), —NHC(O)R^(a1),—NHC(S)R^(a1), —NR^(a2)C(O)R^(a1), —NR^(a1)C(S)R^(a2), —NHS(O)₂R^(a1),—NR^(a1)S(O)₂R^(a2), —NHC(O)NHR^(a1), —NHC(S)NHR^(a1), —NR^(a1)C(O)NH₂,—NR^(a1)C(S)NH₂, —NR^(a1)C(O) NHR^(a2), —NR^(a1)C(S)NHR^(a2),—NHC(O)NR^(a1)R^(a2), —NHC(S)NR^(a1)R^(a2), —NR^(a1)C(O)NR^(a2)R^(a3),—NR^(a3)C(S)NR^(a1)R^(a2), —NH S(O)₂NHR^(a1), —NR^(a1) S(O)₂NH₂,—NR^(a1) S(O)₂NHR^(a2), —NHS(O)₂NR^(a1)R^(a2), —NR^(a1)S(O)₂NR^(a2)R^(a3), —NHR^(a1), and —NR^(a1)R^(a2) in a number rangingfrom zero to (2n′+1), where n′ is the total number of carbon atoms insuch group. R^(a1), R^(a2) and R^(a3) each independently refer tohydrogen, C₁₋₈ alkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, aryl substituted with 1-3 halogens, C₁₋₈ alkoxy,haloalkyl, haloalkoxy or C₁₋₈ thioalkoxy groups, or unsubstitutedaryl-C₁₋₄ alkyl groups. R^(a1), R^(a2) and R^(a3) can be furthersubstituted with R^(b1), halogen, —OH, —NH₂, —NO₂, —CN, —C(O)OH,—C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂,—NHS(O)₂NH₂, —C(NH)NH₂, —OR^(b1), —SR^(b1), —OC(O)R^(b1), —OC(S)R^(b1),—C(O)R^(b1), —C(S)R^(b1), —C(O)OR^(b1), —C(S)OR^(b1), —S(O)R^(b1),—S(O)₂R^(b1), —C(O)NHR^(b1), —C(S)NHR^(b1), —C(O)NR^(b1)R^(b2),—C(S)NR^(b1)R^(b2), —S(O)₂NHR^(b1), —S(O)₂NR^(b1)R^(b2), —C(NH)NHR^(b1),—C(NH)NR^(b1)R^(b2), —NHC(O)R^(b1), —NHC(S)R^(b1), —NR^(b2)C(O)R^(b1),—NR^(b1)C(S)R^(b2), —NHS(O)₂R^(b1), —NR^(b1) S(O)₂R^(b2),—NHC(O)NHR^(b1), —NHC(S)NHR^(b1), —NR^(b1)C(O)NH₂, —NR^(b1)C(S)NH,—NR^(b1)C(O)NHR^(b2), —NR^(b1)C(S)NHR^(b2), —NHC(O)NR^(b1)R^(b2),—NHC(S)NR^(b1)R^(b2), —NR^(b1)C(O)NR^(b2)R^(b3),—NR^(b3)C(S)NR^(b1)R^(b2), —NHS(O)₂NHR^(b1), —NR^(b1) S(O)₂NH₂,—NR^(b1)S(O)₂NHR^(b2), —NHS(O)₂NR^(b1)R^(b2), —NR^(b1)S(O)₂NR^(b2)R^(b3), —NHR^(b1), and —NR^(b1)R^(b2) in a number rangingfrom zero to (2p′+1), where p′ is the total number of carbon atoms insuch group. R^(b1), R^(b2) and R^(b3) each independently refer tohydrogen, C₁₋₈ alkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, aryl substituted with 1-3 halogens, C₁₋₈ alkoxy,haloalkyl, haloalkoxy or C₁₋₈ thioalkoxy groups, or unsubstitutedaryl-C₁₋₄ alkyl groups.

Substituents for the aryl and heteroaryl groups are varied and aregenerally selected from: R′, halogen, —OH, —NH₂, —NO₂, —CN, —C(O)OH,—C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂,—NHS(O)₂NH₂, —C(NH)NH₂, —OR′, —SR′, —OC(O)R′, —OC(S)R′, —C(O)R′,—C(S)R′, —C(O)OR, —C(S)OR′, —S(O)R′, —S(O)₂R′, —C(O)NHR′, —C(S)NHR′,—C(O)NR′R″, —C(S)NR′R″, —S(O)₂NHR′, —S(O)₂NR′R″, —C(NH)NHR′,—C(NH)NR′R″, —NHC(O)R′, —NHC(S)R′, —NR″C(O)R′, —NR′C(S)R″, —NHS(O)₂R′,—NR′S(O)₂R″, —NHC(O)NHR′, —NHC(S)NHR′, —NR′C(O)NH₂, —NR′C(S)NH₂,—NR′C(O)NHR″, —NR′C(S)NH R″, —NHC(O)NR′R″, —NHC(S)NR′R″, —NR′C(O)NR′R′″,—NR′″C(S)NR′R″, —NHS(O)₂NHR′, —NR′S(O)₂N H₂, —NR′S(O)₂NHR″,—NHS(O)₂NR′R″, —NR′S(O)₂NR″R′″, —NHR′, —NR′R″, —N₃,perfluoro(C₁-C₄)alkoxy, and perfluoro(C₁-C₄)alkyl, in a number rangingfrom zero to the total number of open valences on the aromatic ringsystem; and where R′, R″ and R′″ are independently selected fromhydrogen, haloalkyl, haloalkoxy, C₁₋₈ alkyl, C₃₋₆ cycloalkyl,cycloalkylalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, aryl-C₁₋₄ alkyl, and aryloxy-C₁₋₄ alkyl.Other suitable substituents include each of the above aryl substituentsattached to a ring atom by an alkylene tether of from 1-4 carbon atoms.R′, R″ and R′″ can be further substituted with R^(a1), halogen, —OH,—NH₂, —NO₂, —CN, —C(O)OH, —C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂,—NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —C(NH)NH₂, —OR^(a1), —SR^(a1),—OC(O) R^(a1), —OC(S)R^(a1), —C(O)R^(a1), —C(S)R^(a1), —C(O)OR^(a1),—C(S)OR^(a1), —S(O)R^(a1), —S(O)₂R^(a1), —C(O)NHR^(a1), —C(S)NHR^(a1),—C(O)NR^(a1)R^(a2), —C(S)NR^(a1)R^(a2),—S(O)₂NHR^(a1),—S(O)₂NR^(a1)R^(a2), —C(NH)NHR^(a1), —C(NH)NR^(a1)R^(a2), —NHC(O)R^(a1),—NHC(S)R^(a1), —NR^(a2)C(O)R^(a1), —NR^(a1)C(S)R^(a2), —NHS(O)₂R^(a1),—NR^(a1) S(O)₂R^(a2), —NHC(O)NHR^(a1), —NHC(S)NHR^(a1), —NR^(a1)C(O)NH₂,—NR^(a1)C(S)NH₂, —NR^(a1)C(O)NHR^(a2), —NR^(a1)C(S)NHR^(a2),—NHC(O)NR^(a1)R^(a2), —NHC(S)NR^(a1)R^(a2), —NR^(a1)C(O)NR^(a2)R^(a3),—NR^(a3)C(S)NR^(a1)R^(a2), —NHS(O)₂NHR^(a1), —NR^(a1) S(O)₂NH₂, —NR^(a1)S(O)₂NHR^(a2), —NHS(O)₂NR^(a1)R^(a2), —NR^(a1)S(O)₂NR^(a2)R^(a3),—NHR^(a1), —NR^(a1)R^(a2), —N₃, perfluoro(C₁-C₄)alkoxy, andperfluoro(C₁-C₄)alkyl, in a number ranging from zero to the total numberof open valences on the aromatic ring system; and where R^(a1), R^(a2)and R^(a3) are each independently selected from hydrogen, haloalkyl,haloalkoxy, C₁₋₈ alkyl, C₃₋₆ cycloalkyl, cycloalkylalkyl, C₂ alkenyl,C₂₋₈ alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryl-C₁₋₄alkyl, or aryloxy-C₁₋₄ alkyl. Other suitable substituents include eachof the above aryl substituents attached to a ring atom by an alkylenetether of from 1-4 carbon atoms.

When two substituents are present on adjacent atoms of a substitutedaryl or a substituted heteroaryl ring, such substituents may optionallybe replaced with a substituent of the formula -T-C(O)—(CH₂)_(q)—U—,wherein T and U are independently —NH—, —O—, —CH₂— or a single bond, andq is an integer of from 0 to 2. Alternatively, when two substituents arepresent on adjacent atoms of a substituted aryl or a substitutedheteroaryl ring, such substituents may optionally be replaced with asubstituent of the formula -A-(CH₂), —B—, wherein A and B areindependently —CH₂—, —O—, —NH—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or asingle bond, and r is an integer of from 1 to 3. One of the single bondsof the new ring so formed may optionally be replaced with a double bond.Alternatively, when two substituents are present on adjacent atoms of asubstituted aryl or a substituted heteroaryl ring, such substituents mayoptionally be replaced with a substituent of the formula—(CH₂)_(s)—X—(CH₂)_(t)—, where s and t are independently integers offrom 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—.The substituent R′ in —NR′— and —S(O)₂NR′— is selected from hydrogen orunsubstituted C₁₋₆ alkyl.

“Protecting group” refers to a grouping of atoms that when attached to areactive group in a molecule masks, reduces or prevents that reactivity.Examples of protecting groups can be found in T. W. Greene and P. G.Wuts, PROTECTIVE GROUPS IN ORGANIC CHEMISTRY, (Wiley, 4th ed. 2006),Beaucage and Iyer, Tetrahedron 48:2223-2311 (1992), and Harrison andHarrison et al., COMPENDIUM OF SYNTHETIC ORGANIC METHODS, Vols. 1-8(John Wiley and Sons. 1971-1996). Representative amino protecting groupsinclude formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl(CBZ), tert-butoxycarbonyl (Boc), trimethyl silyl (TMS),2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted tritylgroups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC),nitro-veratryloxycarbonyl (NVOC), tri-isopropylsilyl (TIPS),phenylsulphonyl and the like (see also, Boyle, A. L. (Editor),carbamates, amides, N-sulfonyl derivatives, groups of formula —C(O)OR,wherein R is, for example, methyl, ethyl, t-butyl, benzyl, phenylethyl,CH₂═CHCH₂—, and the like, groups of the formula —C(O)R′, wherein R′ is,for example, methyl, phenyl, trifluoromethyl, and the like, groups ofthe formula —SO₂R″, wherein R″ is, for example, tolyl, phenyl,trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl,2,3,6-trimethyl-4-methoxyphenyl, and the like, and silanyl containinggroups, such as 2-trimethylsilylethoxymethyl, t-butyldimethylsilyl,triisopropylsilyl, and the like, CURRENT PROTOCOLS IN NUCLEIC ACIDCHEMISTRY, John Wiley and Sons, New York, Volume 1, 2000).

As used herein, the term “composition” refers to a formulation suitablefor administration to an intended animal subject for therapeuticpurposes that contains at least one pharmaceutically active compound andat least one pharmaceutically acceptable carrier or excipient.

The term “pharmaceutically acceptable” indicates that the indicatedmaterial does not have properties that would cause a reasonably prudentmedical practitioner to avoid administration of the material to apatient, taking into consideration the disease or conditions to betreated and the respective route of administration. For example, it iscommonly required that such a material be essentially sterile, e.g., forinjectables.

“Pharmaceutically acceptable salt” refers to a salt which is acceptablefor administration to a patient, such as a mammal (e.g., salts havingacceptable mammalian safety for a given dosage regime). Such salts canbe derived from pharmaceutically-acceptable inorganic or organic basesand from pharmaceutically-acceptable inorganic or organic acids,depending on the particular substituents found on the compoundsdescribed herein. When compounds disclosed herein contain relativelyacidic functionalities, base addition salts can be obtained bycontacting the neutral form of such compounds with a sufficient amountof the desired base, either neat or in a suitable inert solvent. Saltsderived from pharmaceutically-acceptable inorganic bases includealuminum, ammonium, calcium, copper, ferric, ferrous, lithium,magnesium, manganic, manganous, potassium, sodium, zinc and the like.Salts derived from pharmaceutically-acceptable organic bases includesalts of primary, secondary, tertiary and quaternary amines, includingsubstituted amines, cyclic amines, naturally-occurring amines and thelike, such as arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lysine, methylglucamine, morpholine,piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine, tromethamineand the like. When compounds disclosed herein contain relatively basicfunctionalities, acid addition salts can be obtained by contacting theneutral form of such compounds with a sufficient amount of the desiredacid, either neat or in a suitable inert solvent. Salts derived frompharmaceutically-acceptable acids include acetic, ascorbic,benzenesulfonic, benzoic, camphosulfonic, citric, ethanesulfonic,fumaric, gluconic, glucoronic, glutamic, hippuric, hydrobromic,hydrochloric, isethionic, lactic, lactobionic, maleic, malic, mandelic,methanesulfonic, mucic, naphthalenesulfonic, nicotinic, nitric, pamoic,pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonicand the like.

Also included are salts of amino acids such as arginate and the like,and salts of organic acids like glucuronic or galactunoric acids and thelike (see, for example, Berge, S. M. et al, “Pharmaceutical Salts”, J.Pharmaceutical Science, 1977, 66:1-19). Certain specific compoundsdisclosed herein contain both basic and acidic functionalities thatallow the compounds to be converted into either base or acid additionsalts.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the disclosure.

In the present context, the term “therapeutically effective” or“effective amount” indicates that the materials or amount of material iseffective to prevent, alleviate, or ameliorate one or more symptoms of adisease or medical condition, and/or to prolong the survival of thesubject being treated. The therapeutically effective amount will varydepending on the compound, the disease, disorder or condition and itsseverity and the age, weight, etc., of the mammal to be treated. Ingeneral, satisfactory results in subjects are indicated to be obtainedat a daily dosage of from about 0.1 to about 10 g/kg subject bodyweight. In some embodiments, a daily dose ranges from about 0.10 to 10.0mg/kg of body weight, from about 1.0 to 3.0 mg/kg of body weight, fromabout 3 to 10 mg/kg of body weight, from about 3 to 150 mg/kg of bodyweight, from about 3 to 100 mg/kg of body weight, from about 10 to 100mg/kg of body weight, from about 10 to 150 mg/kg of body weight, or fromabout 150 to 1000 mg/kg of body weight. The dosage can be convenientlyadministered, e.g., in divided doses up to four times a day or insustained-release form.

In the present context, the terms “synergistically effective” or“synergistic effect” indicate that two or more compounds that aretherapeutically effective, when used in combination, provide improvedtherapeutic effects greater than the additive effect that would beexpected based on the effect of each compound used by itself.

By “assaying” is meant the creation of experimental conditions and thegathering of data regarding a particular result of the exposure tospecific experimental conditions. For example, enzymes can be assayedbased on their ability to act upon a detectable substrate. A compoundcan be assayed based on its ability to bind to a particular targetmolecule or molecules.

As used herein, the terms “ligand” and “modulator” are used equivalentlyto refer to a compound that changes (i.e., increases or decreases) theactivity of a target biomolecule, e.g., an enzyme such as a kinase.Generally a ligand or modulator will be a small molecule, where “smallmolecule refers to a compound with a molecular weight of 1500 Daltons orless, or preferably 1000 Daltons or less, 800 Daltons or less, or 600Daltons or less. Thus, an “improved ligand” is one that possesses betterpharmacological and/or pharmacokinetic properties than a referencecompound, where “better” can be defined by one skilled in the relevantart for a particular biological system or therapeutic use.

The term “binds” in connection with the interaction between a target anda potential binding compound indicates that the potential bindingcompound associates with the target to a statistically significantdegree as compared to association with proteins generally (i.e.,non-specific binding). Thus, the term “binding compound” refers to acompound that has a statistically significant association with a targetmolecule. Preferably a binding compound interacts with a specifiedtarget with a dissociation constant (K_(D)) of 1 mM or less, 1 μM orless, 100 nM or less, 10 nM or less, or 1 nM or less.

In the context of compounds binding to a target, the terms “greateraffinity” and “selective” indicates that the compound binds more tightlythan a reference compound, or than the same compound in a referencecondition, i.e., with a lower dissociation constant. In someembodiments, the greater affinity is at least 2, 3, 4, 5, 8, 10, 50,100, 200, 400, 500, 1000, or 10,000-fold greater affinity. The term“selective” also refers to a compound that selectively inhibits RAFkinase relative to other 287 kinases, i.e. a compound having an IC₅₀ ofless than 500 nm, less than 100 nM, less than 50 nM, less than 20 nM,less than 10 nM, less than 5 nM, or less than 1 nM as determined in agenerally accepted RAF kinase activity assay and when determined in acomparable generally accepted other kinases activity assay will have aratio of IC₅₀ for other kinases divided by the IC₅₀ for RAF kinaseof >20, also >30, also >40, also >50, also >60, also >70, also >80,also >90, also >100. Such compounds are effective in treating a diseaseor condition that is RAF protein kinase mediated, without effectingother protein kinases. Such compounds are preferably, but notnecessarily, selective with respect to other protein kinases, i.e. whencompared to another protein kinase, the IC₅₀ for the other kinasedivided by the IC₅₀ for RAF kinase is >20, also >30, also >40, also >50,also >60, also >70, also >80, also >90, also >100. Preferably, thecompounds are selective relative to other protein kinases including, butnot limited to, wild type BRAF and CRAF kinases. While it is understoodthat a RAF selective inhibitor may be used to treat any RAF proteinkinase mediated disease or condition, the RAF selectivity providesbeneficial effects in treating certain diseases or conditions,including, but not limiting to, melanoma, metastatic melanoma, thyroidcancer, lung cancer, colorectal cancer and ovarian cancer.

As used herein in connection with compounds disclosed herein, the term“synthesizing” and like terms means chemical synthesis from one or moreprecursor materials. Further, by “assaying” is meant the creation ofexperimental conditions and the gathering of data regarding a particularresult of the experimental conditions. For example, enzymes can beassayed based on their ability to act upon a detectable substrate. Acompound or ligand can be assayed based on its ability to bind to aparticular target molecule or molecules.

As used herein, the term “modulating” or “modulate” or “regulating”refers to an effect of altering a biological activity, especially abiological activity associated with a particular biomolecule such as aprotein kinase. For example, an agonist or antagonist of a particularbiomolecule modulates the activity of that biomolecule, e.g., an enzyme,by either increasing (e.g. agonist, activator), or decreasing (e.g.antagonist, inhibitor) the activity of the biomolecule, such as anenzyme. Such activity is typically indicated in terms of an inhibitoryconcentration (IC₅₀) or excitation concentration (EC₅₀) of the compoundfor an inhibitor or activator, respectively, with respect to, forexample, an enzyme.

“Prodrugs” means any compound which releases an active parent drugaccording to Formula I in vivo when such prodrug is administered to amammalian subject. Prodrugs of a compound of Formula I or a compound ofany of the subgeneric formulas are prepared by modifying functionalgroups present in the compound of Formula I or a compound of any of thesubgeneric formulas in such a way that the modifications may be cleavedin vivo to release the parent compound. Prodrugs may be prepared bymodifying functional groups present in the compounds in such a way thatthe modifications are cleaved, either in routine manipulation or invivo, to the parent compounds. Prodrugs include compounds of Formula Ior a compound of any of the subgeneric formulas, wherein a hydroxy,amino, carboxyl or sulfhydryl group in a compound of Formula I is bondedto any group that may be cleaved in vivo to regenerate the freehydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugsinclude, but are not limited to esters (e.g., acetate, formate, andbenzoate derivatives), amides, guanidines, carbamates (e.g.,N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds ofFormula I, or a compound of any of the subgeneric formulas, and thelike. Preparation, selection, and use of prodrugs is discussed in T.Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 ofthe A.C.S. Symposium Series; “Design of Prodrugs”, ed. H. Bundgaard,Elsevier, 1985; and in Bioreversible Carriers in Drug Design, ed. EdwardB. Roche, American Pharmaceutical Association and Pergamon Press, 1987,each of which are hereby incorporated by reference in their entirety.

Esters a compound of Formula I or a compound of any of the subgenericformulas can be prepared through functionalization of hydroxyl and/orcarboxyl groups that may be present within the molecular structure ofthe compound. Amides and prodrugs can also be prepared using techniquesknown to those skilled in the art. For example, amides may be preparedfrom esters, using suitable amine reactants, or they may be preparedfrom anhydride or an acid chloride by reaction with ammonia or a loweralkyl amine. Moreover, esters, urease, sulfonamides, and amides of acompound of Formula I or a compound of any of the subgeneric formulascan be made by reaction with a carbonylating agent (e.g., ethyl formate,acetic anhydride, methoxyacetyl chloride, benzoyl chloride, methylisocyanate, ethyl chloroformate) or methanesulfonyl chloride and asuitable base (e.g., 4-dimethylaminopyridine, pyridine, triethylamine,potassium carbonate) in a suitable organic solvent (e.g.,tetrahydrofuran, acetone, methanol, pyridine, N,N-dimethylformamide) ata temperature of from 0 to 60° C. Prodrugs are typically prepared bycovalent attachment of a moiety, which results in a compound that istherapeutically inactive until modified by an individual's metabolicsystem.

“Tautomer” means compounds produced by the phenomenon wherein a protonof one atom of a molecule shifts to another atom. See, Jerry March,Advanced Organic Chemistry: Reactions, Mechanisms and Structures, FourthEdition, John Wiley & Sons, pages 69-74 (1992). The tautomers also referto one of two or more structural isomers that exist in equilibrium andare readily converted from one isomeric form to another. Examples ofinclude keto-enol tautomers, such as acetone/propen-2-ol, imine-enaminetautomers and the like, ring-chain tautomers, such asglucose/2,3,4,5,6-pentahydroxy-hexanal and the like, the tautomericforms of heteroaryl groups containing a —N═C(H)—NH— ring atomarrangement, such as pyrazoles, imidazoles, benzimidazoles, triazoles,and tetrazoles. Where the compound contains, for example, a keto oroxime group or an aromatic moiety, tautomeric isomerism (‘tautomerism’)can occur. The compounds described herein may have one or more tautomersand therefore include various isomers. A person of ordinary skill in theart would recognize that other tautomeric ring atom arrangements arepossible. All such isomeric forms of these compounds are expresslyincluded in the this disclosure.

“Isomers” mean compounds having identical molecular formulae but differin the nature or sequence of bonding of their atoms or in thearrangement of their atoms in space. Isomers that differ in thearrangement of their atoms in space are termed “stereoisomers”.“Stereoisomer” and “stereoisomers” refer to compounds that exist indifferent stereoisomeric forms if they possess one or more asymmetriccenters or a double bond with asymmetric substitution and, therefore,can be produced as individual stereoisomers or as mixtures.Stereoisomers include enantiomers and diastereomers. Stereoisomers thatare not mirror images of one another are termed “diastereomers” andthose that are non-superimposable mirror images of each other are termed“enantiomers”. When a compound has an asymmetric center, for example, itis bonded to four different groups, a pair of enantiomers is possible.An enantiomer can be characterized by the absolute configuration of itsasymmetric center and is described by the R- and S-sequencing rules ofCahn and Prelog, or by the manner in which the molecule rotates theplane of polarized light and designated as dextrorotatory orlevorotatory (i.e., as (+) or (−)-isomers respectively). A chiralcompound can exist as either individual enantiomer or as a mixturethereof. A mixture containing equal proportions of the enantiomers iscalled a “racemic mixture”. Unless otherwise indicated, the descriptionis intended to include individual stereoisomers as well as mixtures. Themethods for the determination of stereochemistry and the separation ofstereoisomers are well-known in the art (see discussion in Chapter 4 ofADVANCED ORGANIC CHEMISTRY, 6th edition J. March, John Wiley and Sons,New York, 2007) differ in the chirality of one or more stereocenters.

Certain compounds disclosed herein can exist in unsolvated forms as wellas solvated forms, including hydrated forms. “Hydrate” refers to acomplex formed by combination of water molecules with molecules or ionsof the solute. “Solvate” refers to a complex formed by combination ofsolvent molecules with molecules or ions of the solute. The solvent canbe an organic compound, an inorganic compound, or a mixture of both.Solvate is meant to include hydrate. Some examples of solvents include,but are not limited to, methanol, N,N-dimethylformamide,tetrahydrofuran, dimethylsulfoxide, and water. In general, the solvatedforms are equivalent to unsolvated forms and are encompassed within thescope of the present disclosure. Certain compounds disclosed herein mayexist in multiple crystalline or amorphous forms. In general, allphysical forms are equivalent for the uses contemplated by thisdisclosure and are intended to be within the scope of the presentdisclosure.

In the context of the use, testing, or screening of compounds that areor may be modulators, the term “contacting” means that the compound(s)are caused to be in sufficient proximity to a particular molecule,complex, cell, tissue, organism, or other specified material thatpotential binding interactions and/or chemical reaction between thecompound and other specified material can occur.

As used herein, the term “subject” refers to a living organism that istreated with compounds as described herein, including, but not limitedto, any mammal, such as a human, other primates, sports animals, animalsof commercial interest such as cattle, farm animals such as horses, orpets such as dogs and cats.

“Solid form” refers to a solid preparation (i.e. a preparation that isneither gas nor liquid) of a pharmaceutically active compound that issuitable for administration to an intended animal subject fortherapeutic purposes. The solid form includes any complex, such as asalt, co-crystal or an amorphous complex, as well as any polymorph ofthe compound. The solid form may be substantially crystalline,semi-crystalline or substantially amorphous. The solid form may beadministered directly or used in the preparation of a suitablecomposition having improved pharmaceutical properties. For example, thesolid form may be used in a formulation comprising at least onepharmaceutically acceptable carrier or excipient.

“Pain” or a “pain condition” can be acute and/or chronic pain,including, without limitation, arachnoiditis; arthritis (e.g.osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, gout);back pain (e.g. sciatica, ruptured disc, spondylolisthesis,radiculopathy); burn pain; cancer pain; dysmenorrhea; headaches (e.g.migraine, cluster headaches, tension headaches); head and facial pain(e.g. cranial neuralgia, trigeminal neuralgia); hyperalgesia;hyperpathia; inflammatory pain (e.g. pain associated with irritablebowel syndrome, inflammatory bowel disease, ulcerative colitis, Crohn'sdisease, cystitis, pain from bacterial, fungal or viral infection);keloid or scar tissue formation; labor or delivery pain; muscle pain(e.g. as a result of polymyositis, dermatomyositis, inclusion bodymyositis, repetitive stress injury (e.g. writer's cramp, carpal tunnelsyndrome, tendonitis, tenosynovitis)); myofascial pain syndromes (e.g.fibromyalgia); neuropathic pain (e.g. diabetic neuropathy, causalgia,entrapment neuropathy, brachial plexus avulsion, occipital neuralgia,gout, reflex sympathetic dystrophy syndrome, phantom limb orpost-amputation pain, postherpetic neuralgia, central pain syndrome, ornerve pain resulting from trauma (e.g. nerve injury), disease (e.g.diabetes, multiple sclerosis, Guillan-Barre Syndrome, myasthenia gravis,neurodegenerative diseases such as Parkinson's disease, Alzheimer'sdisease, amyotrophic lateral sclerosis, or cancer treatment); painassociated with skin disorders (e.g. shingles, herpes simplex, skintumors, cysts, neurofibromatosis); sports injuries (e.g. cuts, sprains,strains, bruises, dislocations, fractures, spinal cord, head); spinalstenosis; surgical pain; tactile allodynia; temporomandibular disorders;vascular disease or injury (e.g. vasculitis, coronary artery disease,reperfusion injury (e.g. following ischemia, stroke, or myocardialinfarcts)); other specific organ or tissue pain (e.g. ocular pain,corneal pain, bone pain, heart pain, visceral pain (e.g. kidney,gallbladder, gastrointestinal), joint pain, dental pain, pelvichypersensitivity, pelvic pain, renal colic, urinary incontinence); otherdisease associated pain (e.g. sickle cell anemia, AIDS, herpes zoster,psoriasis, endometriosis, asthma, chronic obstructive pulmonary disease(COPD), silicosis, pulmonary sarcoidosis, esophagitis, heart burn,gastroesophageal reflux disorder, stomach and duodenal ulcers,functional dyspepsia, bone resorption disease, osteoporosis, cerebralmalaria, bacterial meningitis); or pain due to graft v. host rejectionor allograft rejections.

As used herein, “MAPK” refers to the mitogen-activated protein kinase.MAPK pathway is an important second signal transduction pathway thataffects HIF-1α level and activity, and may also affect MN/CA9expression. Multiple lines of evidence indicate that the MAPK pathway isimportant in human cancer. This pivotal pathway relays extracellularsignals to the nucleus via a cascade of specific phosphorylation eventsinvolving Ras, Raf, MEK, and ERK to regulate fundamental cellularprocesses, including proliferation, differentiation, and cell survival(Kolch, W., Biochem. J, 351: 289-305 (2000); and Lu and Xu, IUBMB Life,58(11): 621-631 (2006)). Inappropriate Ras activation is associated withnearly a third of all human cancers (Downward, J. Nat Rev Cancer, 3:11-22 (2003)). One of the Raf isoforms, BRAF, is mutated in manycancers, including malignant melanoma (27-70%), papillary thyroid cancer(36-53%), ovarian cancer (30%) and colorectal cancer (5-22%), and themutations are frequently gain-of-function substitutions that result inconstitutive activity Messersmith et al., Clin Adv. Hematol. Oncol.,4(11): 831-836 (2006); Garnett and Marais, Cancer Cell, 6: 313-319(2004)). ERK is elevated in nearly 50% of breast cancers and isassociated with a poor prognosis (Messersmith et al. (2006)).

“Unit dosage form” refers to a composition intended for a singleadministration to treat a subject suffering from a disease or medicalcondition. Each unit dosage form typically comprises each of the activeingredients of this disclosure plus pharmaceutically acceptableexcipients. Examples of unit dosage forms are individual tablets,individual capsules, bulk powders, liquid solutions, ointments, creams,eye drops, suppositories, emulsions or suspensions. Treatment of thedisease or condition may require periodic administration of unit dosageforms, for example: one unit dosage form two or more times a day, onewith each meal, one every four hours or other interval, or only one perday. The expression “oral unit dosage form” indicates a unit dosage formdesigned to be taken orally.

The compounds disclosed herein may also contain unnatural proportions ofatomic isotopes at one or more of the atoms that constitute suchcompounds. For example, the compounds may be radiolabeled withradioactive isotopes, such as for example tritium (³H), iodine-125(¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations of the compoundsdisclosed herein, whether radioactive or not, are intended to beencompassed within the scope of the disclosure.

The term “deuterated” as used herein alone or as part of a group, meanssubstituted deuterium atoms. When a particular position is designated asholding deuterium (stated as “D” or “deuterium”), it is understood thatthe abundance of deuterium at that position is substantially greaterthan the natural abundance of deuterium, which is 0.015% (i.e., at least50.1% incorporation of deuterium).

The term “deuterated analog” as used herein alone or as part of a group,means substituted deuterium atoms in place of hydrogen. The deuteratedanalog of a compound may be a fully or partially deuterium substitutedderivative. Preferably the deuterium substituted compound holds a fullyor partially deuterium substituted alkyl, aryl or heteroaryl group. Inone embodiment, the deuterium substituted compound holds a fully orpartially deuterium substituted alkyl group, e.g., —CD₃, CD₂CD₃,—CD₂CD₂CD₃ (n-propyl-D7), —CD(CD₃)₂ (iso-propyl-D7), —CD₂CD₂CD₂CD₃(n-butyl-D9), —CD₂-CD(CD₃)₂ (iso-butyl-D9) and the like. In anotherembodiment, the deuterium substituted compound holds a fully orpartially deuterium substituted aryl, such as phenyl, e.g., C₆D₅ or afully or partially deuterium substituted heteroaryl, e.g., pyrazoly-d₂,thiazoly-d₂, pyridyl-d₃, and the like.

As used in connection with binding of a compound with a RAF kinase,e.g., BRAF kinase, the term “interact” means that the distance from abound compound to a particular amino acid residue will be 5.0 angstromsor less. In particular embodiments, the distance from the compound tothe particular amino acid residue is 4.5 angstroms or less, 4.0angstroms or less, 3.5 angstroms or less, or 3 angstroms or less. Suchdistances can be determined, for example, using co-crystallography, orestimated using computer fitting of a compound in a BRAF active site.

By “binding site” is meant an area of a target molecule to which aligand can bind non-covalently. Binding sites embody particular shapesand often contain multiple binding pockets' present within the bindingsite. The particular shapes are often conserved within a class ofmolecules, such as a molecular family. Binding sites within a class alsocan contain conserved structures such as, for example, chemicalmoieties, the presence of a binding pocket, and/or an electrostaticcharge at the binding site or some portion of the binding site, all ofwhich can influence the shape of the binding site.

As used herein, “binding pocket” is meant a specific volume within abinding site. A binding pocket can often be a particular shape,indentation, or cavity in the binding site. Binding pockets can containparticular chemical groups or structures that are important in thenoncovalent binding of another molecule such as, for example, groupsthat contribute to ionic, hydrogen bonding, or van der Waalsinteractions between the molecules.

As used herein in connection with amino acid or nucleic acid sequence,the term “isolate” indicates that the sequence is separated from atleast a portion of the amino acid and/or nucleic acid sequences withwhich it would normally be associated.

In connection with amino acid or nucleic sequences, the term “purified”indicates that the subject molecule constitutes a significantly greaterproportion of the biomolecules in a composition than the proportionobserved in a prior composition, e.g., in a cell culture. The greaterproportion can be 2-fold, 5-fold, 10-fold, or more than 10-fold, withrespect to the proportion found in the prior composition.

The disclosure also embraces isotopically-labeled compounds disclosedherein which are identical to those recited herein, but for the factthat one or more atoms are replaced by an atom having an atomic mass ormass number different from the atomic mass or mass number usually foundin nature. Examples of isotopes that can be incorporated into compoundsdisclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, and chlorine, such as, but not limited to ²H(deuterium, D), ³H (tritium), ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F, ³¹P, ³²P, ³⁵S,³⁶Cl and ¹²⁵I. Unless otherwise stated, when a position is designatedspecifically as “H” or “hydrogen”, the position is understood to havehydrogen at its natural abundance isotopic composition or its isotopes,such as deuterium (D) or tritium (³H). Certain isotopically-labeledcompounds disclosed herein (e.g., those labeled with ³H and ¹⁴C) areuseful in compound and/or substrate tissue distribution assays.Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C) isotopes are useful fortheir ease of preparation and detectability. Further, substitution withheavier isotopes such as deuterium (i.e., ²H) may afford certaintherapeutic advantages resulting from greater metabolic stability (e.g.,increased in vivo half-life or reduced dosage requirements) and hencemay be preferred in some circumstances. Isotopically labeled compoundsdisclosed herein can generally be prepared by following proceduresanalogous to those disclosed in the Schemes and in the Examples hereinbelow, by substituting an isotopically labeled reagent for anon-isotopically labeled reagent.

II. General

The present disclosure concerns compounds and methods for modulating,regulating, mediating or inhibiting MAPK pathway signaling by regulatingthe interaction of a RAF inhibitor with a mutant RAF kinase, forexample, by selective inhibition of mutant BRAF protein kinases.Surprisingly, the inhibition of a wild type RAF kinase with thecompounds as described herein does not induce or cause the activation ofMAPK pathway as observed by pERK or pMEK, for instance, in cells havingRAS mutation or upstream receptor tyrosine kinase activation.

III. Compounds

In one aspect, the disclosure provides a compound having formula (I):

wherein the variables and substituents are as defined in the Summary

In some embodiments of compounds of formula (I), the compounds havemolecular weights less than 800, preferably, the compounds havemolecular weights less than 750, more preferably, the compounds havemolecular weights less than 700, even more preferably, the compoundshave molecular weights less than 650, still more preferably, thecompounds have molecular weights less than 600. In certain preferredembodiments, the compounds have molecular weights less than 550. Inother preferred embodiments, the compounds have molecular weights lessthan 500. In yet other preferred embodiments, the compounds havemolecular weights less than 450.

In some embodiments of compounds of formula (I), Z is optionallysubstituted aryl or optionally substituted heteroaryl, with the provisothat Z is other than an optionally substituted

core when R⁴ is attached at the ortho position with respect to the -L-Zsubstituent on the phenyl ring, wherein the wavy line indicates thepoint of attachment to the rest of the molecule. In certain embodiments,Z is other than an optionally substituted

core. In certain embodiments, Z is other than a 5-position optionallysubstituted

core when R⁴ is attached at the ortho position with respect to the -L-Zsubstituent on the phenyl ring. In one embodiment, Z is an optionallysubstituted aryl. In another embodiment, Z is an optionally substitutedheteroaryl. All the other variables in formula (I) are as defined in anyof the embodiments as described herein.

In some embodiments of compounds of formula (I), Z is an aryl orheteroaryl, each of which is independently optionally substituted withfrom 1-5 R⁷ substituents; each R⁷ is independently selected from C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₃₋₈ cycloalkyl,C₃₋₈ cycloalkyl-C₁₋₄-alkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, heterocycloalkyl-C₁₋₄ alkyl or—R^(a), wherein R^(a) is selected from halogen, —CH═CH₂, —CN, —OH, —NH₂,—NO₂, —C(O)OH, —C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂,—NHC(S)NH₂, —NHS(O)₂NH₂, —C(NH)NH₂, —OR^(b), —SR^(b), —OC(O)R^(b),—OC(S)R^(b), —C(O)R^(b), —C(S)R^(b), —C(O)OR^(b), —C(S)OR^(b),—S(O)R^(b), —S(O)₂R^(b), —C(O)NHR^(b), —C(S)NHR^(b), —C(O)NR^(b)R^(b),—C(S)NR^(b)R^(b), —S(O)₂NHR^(b), —S(O)₂NR^(b)R^(b), —C(NH)NHR^(b),—C(NH)NR^(b)R^(b), —NHC(O)R^(b), —NHC(S)R^(b), —NR^(b)C(O)R^(b),—NR^(b)C(S)R^(b), —NHS(O)₂R^(b), —NR^(b)S(O)₂R^(b), —NHC(O)N HR^(b),—NHC(S)NHR^(b), —NR^(b)C(O)NH₂, —NR^(b)C(S)NH₂, —NR^(b)C(O)NHR^(b),—NR^(b)C(S)NHR^(b), —NHC(O)NR^(b)R^(b), —NHC(S)NR^(b)R^(b),—NR^(b)C(O)NR^(b)R^(b), —NR^(b)C(S)NR^(b)R^(b), —NHS(O)₂NHR^(b),—NR^(b)S(O)₂NH₂, —NR^(b)S(O)₂NHR^(b), —NHS(O)₂NR^(b)R^(b),—NR^(b)S(O)₂NR^(b)R^(b), —NHR^(b) or —NR^(b)R^(b), wherein each R^(b) isindependently selected from the group consisting of C₁₋₆alkyl, halogen,—CN, C₁₋₆alkoxy, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₄-alkyl, —OH,C₁₋₆haloalkyl, C₁₋₆haloalkoxy, aryl, aryl-C₁₋₄alkyl, heteroaryl andheteroarylalkyl; or two R^(b) substituents when attached to the samenitrogen atom taken together with the nitrogen atom form a three toeight-membered ring having from 0-2 additional heteroatoms as ringmembers selected from N, O or S; wherein the aliphatic or aromaticportion of R⁷ is further optionally substituted with from 1-3 groupsselected from C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl,heterocycloalkyl-C₁₋₄alkyl or —R^(c), wherein each R^(c) isindependently selected from halogen, —CH═CH₂, —CN, —OH, —NH₂, —NO₂,—C(O)OH, —C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂,—NHS(O)₂NH₂, —C(NH)NH₂, —OR^(d), —SR^(d), —OC(O)R^(d), —OC(S)R^(d),—C(O)R^(d), —C(S)R^(d), —C(O)OR^(d), —C(S)OR^(d), —S(O)R^(d),—S(O)₂R^(d), —C(O)NHR^(d), —C(S)NHR^(d), —C(O)NR^(d)R^(d),—C(S)NR^(d)R^(d), —S(O)₂NHR^(d), —S(O)₂NR^(d)R^(d), —C(NH)NHR^(d),—C(NH)NR^(d)R^(d), —NHC(O)R^(d), —NHC(S)R^(d), —NR^(d)C(O)R^(d),—NR^(d)C(S)R^(d), —NHS(O)₂R^(d), —NR^(d)S(O)₂R^(d), —NHC(O)N HR^(d),—NHC(S)NHR^(d), —NR^(d)C(O)NH₂, —NR^(d)C(S)NH₂, —NR^(d)C(O)NHR^(d),—NR^(d)C(S)NHR^(d), —NHC(O)NR^(d)R^(d), —NHC(S)NR^(d)R^(d),—NR^(d)C(O)NR^(d)R^(d), —NR^(d)C(S)NR^(d)R^(d), —NHS(O)₂NHR^(d),—NR^(d)S(O)₂NH₂, —NR^(d)S(O)₂NHR^(d), —NHS(O)₂NR^(d)R^(d),—NR^(d)S(O)₂NR^(d)R^(d), —NHR^(d), R^(f) or —NR^(d)R^(d), wherein eachR^(d) is independently selected from C₁₋₆ alkyl, arylalkyl, aryl,heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl or heterocycloalkylalkyl; and wherein the aromaticportion of R^(d) is optionally substituted with from 1-3 substituentsindependently selected from R^(e), wherein R^(e) is selected from thegroup consisting of halogen, —CH═CH₂, —CN, —OH, —NH₂, —NO₂, —C(O)OH,—C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂,—NHS(O)₂NH₂, —C(NH)NH₂, —OR^(f), —SR^(f), —OC(O)R^(f), —OC(S)R^(f),—C(O)R^(f), —C(S)R^(f), —C(O)OR^(f), —C(S)OR^(f), —S(O)R^(f),—S(O)₂R^(f), —C(O)NHR^(f), —C(S)NHR^(f), —C(O)NR^(f)R^(f),—C(S)NR^(f)R^(f), —S(O)₂NHR^(f), —S(O)₂NR^(f)R^(f), —C(NH)NHR^(f),—C(NH) NR^(f)R^(f), —NHC(O)R^(f), —NHC(S)R^(f), —NR^(f)C(O)R^(f),—NR^(f)C(S)R^(f), —NHS(O)₂R^(f), —NR^(f)S(O)₂R^(f), —NHC(O)NHR^(f), —NHC(S)NHR^(f), —NR^(f)C(O)NH₂, —NR^(f)C(S)NH₂, —NR^(f)C(O)NHR^(f),—NR^(f)C(S)NHR^(f), —NHC(O)NR^(f)R^(f), —NHC(S)NR^(f)R^(f),—NR^(f)C(O)NR^(f)R^(f), —NR^(f)C(S)NR^(f)R^(f), —NHS(O)₂NHR^(f),—NR^(f)S(O)₂NH₂, —NR^(f)S(O)₂NHR^(f), —NHS(O)₂NR^(f)R^(f),—NR^(f)S(O)₂NR^(f)R^(f), —NHR^(f), —NR^(f)R^(f) and R^(f), wherein R isC₁₋₆alkyl or aryl; or two adjacent R⁷ groups on the aryl or heteroarylring together with the atoms to which they are attached form a 5- or6-membered ring having from 0 to 2 additional heteroatoms selected fromN, O or S, optionally substituted with from 1 to 3 R^(d) or R^(e)substituents. In some instances, R^(f) is C₁₋₆alkyl. In other instances,R^(f) is aryl, such as phenyl. In some instances, Z is a heteroaryloptionally substituted with from 1-2 R⁷. In other instances, R⁷ is anoptionally substituted 6-membered heteroaryl. The other variables are asdefined in any of the embodiments of compounds of formula (I).

In some embodiments of compounds of formula (I), Z is aryl or heteroarylgroup, wherein the heteroaryl group has from 1 to 4 heteroatoms as ringmembers selected from N, O or S; and wherein the aryl or heteroarylgroups are optionally substituted with from 1 to 3 R⁷ substituents. Inone embodiment, Z is a heteroaryl having from 1-4 heteroatoms as ringmembers selected from N, O or S; and wherein the heteroaryl group isoptionally substituted with from 1 to 2 independently selected R⁷substituents; or 1-2 independently selected R^(a) substituents; or 1-2independently selected R^(b) substituents; or 1-2 independently selectedR^(c) substituents; or 1-2 independently selected R^(d) substituents; or1-2 independently selected R^(e) substituents. In some instances, Z isan optionally substituted 5-membered heteroaryl. In other instances, Zis an optionally substituted 6-membered heteroaryl. In other instances,Z is an optionally substituted bicyclic heteroaryl. The other variablesare as defined in any of the embodiments of compounds of formula (I).

In some embodiments of compounds of formula (I), Z is 2-pyridyl,3-pyridyl, 4-pyridyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,3-pyrazolyl, 1-pyrazolyl, 4-imidazolyl

each of which is optionally substituted, for example, each of which isoptionally substituted with from 1 to 3 independently selected R⁷substituents; or 1-3 independently selected R^(a) substituents; or 1-3independently selected R^(b) substituents; or 1-3 independently selectedR^(c) substituents; or 1-3 independently selected R^(d) substituents; or1-3 independently selected R^(e) substituents; or 1-3 independentlyselected R^(f) substituents. The wavy line indicates the point ofattachment to the rest of the molecule. In certain embodiments, Z isoptionally substituted 4-thiazolyl. In other embodiments, Z isoptionally substituted 3-pyrazolyl. The other variables are as definedin any of the embodiments of compounds of formula (I).

In some embodiments of compounds of formula (I), Z is selected from:

wherein each R²⁰ is independently R⁷; or R^(a); or R^(b); or R^(c); orR^(d); or R^(e); or R^(f); or R^(g), wherein R²⁰ is further optionallysubstituted with from 1-3 R^(e) or 1-3 R^(g) substituents as definedherein. The wavy line indicates the point of attachment to the rest ofthe molecule. In one embodiment, Z is

optionally substituted with from 1-3 independently selected R⁷substituents; or 1-3 independently selected R^(a) substituents; or 1-3independently selected R^(b) substituents; or 1-3 independently selectedR^(c) substituents; or 1-3 independently selected R^(d) substituents; or1-3 independently selected R^(e) substituents; or 1-3 independentlyselected R^(f) substituents. The wavy line indicates the point ofattachment to the rest of the molecule. The other variables are asdefined in any of the embodiments of compounds of formula (I).

In some embodiments of compounds of formula (I), Z is 5-pyrimidinyl,2-pyrimidinyl, 4-pyrimidinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-pyrazinyl, 2-pyridazinyl, 3-pyridazinyl, 1-pyrrolyl, 2-pyrrolyl,3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 1-pyrazolyl, 2-pyrazolyl,3-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl,4-thiazolyl, 5-thiazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl,3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,2,3-triazol-1-yl,1,2,3-triazol-2-yl, 1,2,3-triazol-3-yl, 1,2,3-triazol-4-yl,1,2,3-triazol-5-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-2-yl,1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl, 1,2,4-triazol-5-yl,1-oxa-2,3-diazol-4-yl, 1-oxa-2,3-diazol-5-yl, 1-oxa-2,4-diazol-3-yl,1-oxa-2,4-diazol-5-yl, 1-oxa-2,5-diazol-3-yl, 1-oxa-2,5-diazol-4-yl,1-thia-2,3-diazol-4-yl, 1-thia-2,3-diazol-5-yl, 1-thia-2,4-diazol-3-yl,1-thia-2,4-diazol-5-yl, 1-thia-2,5-diazol-3-yl, 1-thia-2,5-diazol-4-yl,1-tetrazolyl, 3-tetrazolyl, 1H-5-tetrazolyl, 3H-5-tetrazolyl, 2-furanyl,3-furanyl, 2-thiopenyl or 3-thiophenyl, each of which is optionallysubstituted with from 1 to 3 independently selected R⁷ substituents; or1 to 3 independently selected R^(a) substituents; or 1 to 3independently selected R^(b) substituents; or 1 to 3 independentlyselected R^(c) substituents; or 1 to 3 independently selected R^(d)substituents; or 1 to 3 independently selected R^(e) substituents; 1 to3 independently selected R^(f) substituents; or 1 to 3 independentlyselected R^(g) substituents selected from F, Cl, Br, I, —CN, —OH, —CF₃,—NH₂, CF₃O—, C₁₋₆alkyl, C₁₋₆alkoxy, CH₃—, CH₃O, —NO₂, t-butyl, phenyl,cyclopropyl, cyclopropylmethyl, cyclopropylamino, pyrimidinyl,4-pyrimidinyl, cyclopropylmethylamino, 1-cyanocyclopropyl, methylamino,dimethylamino, methylthio, acetoxy, acetyl, methoxycarbonyl, acetamido,1-cyclopropylethyl, 2-cyclopropylethyl, 1-cyclopropylethylamino,2-cyclopropylethylamino, 1-hydroxy-1-methylethyl, methylcarbamoyl,1-carboxycyclopropyl, 1-carbamoylcyclopropyl,1-methoxycarbonylcyclopropyl, 1-cyanoisopropyl, 1-hydroxycyclopropyl,1-hydoxyisopropyl, cyclobutoxy, cyclopentoxy, cycloheyloxy,4-morpholino, thiomorpholin-4-yl, 4-hydroxypiperidinyl, 1-piperidinyl,piperazinyl, 4-methylpiperazinyl, 4-t-butoxycarbonylpiperazinyl,azetidinyl, pyrrolidinyl, cyclopropylcarbamoyl,5-methyl-1,2,4-oxadiazol-3-yl, 5-methyl-1,3,4-oxadiazol-2yl,5-dimethylamino-1,3,4-oxadiazol-2yl, 2-(methoxycarbonylamino)propyl or5-methylamino-1,3,4-thiadiazol-2-yl. In some instances, R^(g) is furtheroptionally substituted with 1-3 R^(e) groups.

In some embodiments of compounds of formula (I), Z is 1-pyrrolyl,2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 1-pyrazolyl,2-pyrazolyl, 3-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl,1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-3-yl,1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-1-yl,1,2,4-triazol-2-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl,1,2,4-triazol-5-yl, 1-oxa-2,3-diazol-4-yl, 1-oxa-2,3-diazol-5-yl,1-oxa-2,4-diazol-3-yl, 1-oxa-2,4-diazol-5-yl, 1-oxa-2,5-diazol-3-yl,1-oxa-2,5-diazol-4-yl, 1-thia-2,3-diazol-4-yl, 1-thia-2,3-diazol-5-yl,1-thia-2,4-diazol-3-yl, 1-thia-2,4-diazol-5-yl, 1-thia-2,5-diazol-3-yl,1-thia-2,5-diazol-4-yl, 1-tetrazolyl, 3-tetrazolyl, 1H-5-tetrazolyl,3H-5-tetrazolyl, 2-furanyl, 3-furanyl, 2-thiopenyl or 3-thiophenyl, eachof which is optionally substituted with from 1 to 3 independentlyselected R⁷ substituents; or 1 to 3 independently selected R^(a)substituents; or 1 to 3 independently selected R^(b) substituents; or 1to 3 independently selected R^(c) substituents; or 1 to 3 independentlyselected R^(d) substituents; or 1 to 3 independently selected R^(e)substituents; 1 to 3 independently selected R^(f) substituents; or 1 to3 independently selected R^(g) substituents selected from F, Cl, Br, I,—CN, —OH, —CF₃, NH₂, CF₃O—, C₁₋₆alkyl, C₁₋₆alkoxy, CH₃—, CH₃O, —NO₂,t-butyl, phenyl, cyclopropyl, cyclopropylmethyl, cyclopropylamino,pyrimidinyl, 4-pyrimidinyl, cyclopropylmethylamino, 1-cyanocyclopropyl,methylamino, dimethylamino, methylthio, acetoxy, acetyl,methoxycarbonyl, acetamido, 1-cyclopropylethyl, 2-cyclopropylethyl,1-cyclopropylethylamino, 2-cyclopropylethylamino,1-hydroxy-1-methylethyl, methylcarbamoyl, 1-carboxycyclopropyl,1-carbamoylcyclopropyl, 1-methoxycarbonylcyclopropyl, 1-cyanoisopropyl,1-hydroxycyclopropyl, 1-hydoxyisopropyl, cyclobutoxy, cyclopentoxy,cycloheyloxy, 4-morpholino, thiomorpholin-4-yl,4-hydroxypiperidinyl,1-piperidinyl, piperazinyl, 4-methylpiperazinyl,4-t-butoxycarbonylpiperazinyl, azetidinyl, pyrrolidinyl,cyclopropylcarbamoyl, 5-methyl-1,2,4-oxadiazol-3-yl,5-methyl-1,3,4-oxadiazol-2yl, 5-dimethylamino-1,3,4-oxadiazol-2yl,2-(methoxycarbonylamino)propyl or 5-methylamino-1,3,4-thiadiazol-2-yl.In some instances, R^(g) is optionally substituted with 1-3 R^(e)groups. In one instance, Z is 4-thiazolyl optionally substituted with1-2 independently selected R⁷ groups; or 1-2 independently selectedR^(a) groups; or 1-2 independently selected R^(b) groups; or 1-2independently selected R^(c) groups; or 1-2 independently selected R^(d)groups; or 1-2 independently selected R^(e) groups; or 1-2 independentlyselected R^(f) groups; or 1-2 independently selected R^(g) groups. Inanother instance, Z is 3-pyrazolyl optionally substituted with 1-2independently selected R⁷ groups; or 1-2 independently selected R^(a)groups; or 1-2 independently selected R^(b) groups; or 1-2 independentlyselected R^(c) groups; or 1-2 independently selected R^(d) groups; or1-2 independently selected R^(e) groups; or 1-2 independently selectedR^(f) groups; or 1-2 independently selected R^(g) groups. In anotherinstances, Z is 2-imidazolyl optionally substituted with 1-2independently selected R⁷ groups; or 1-2 independently selected R^(a)groups; or 1-2 independently selected R^(b) groups; or 1-2 independentlyselected R^(c) groups; or 1-2 independently selected R^(d) groups; or1-2 independently selected R^(e) groups; or 1-2 independently selectedR^(f) groups; or 1-2 independently selected R^(g) groups. In oneinstance, Z is 5(2-aminopyrimidin-4-yl)-4-thiazolyl substituted withfrom 1-2 independently selected R⁷ groups; or 1-2 independently selectedR^(a) groups; or 1-2 independently selected R^(b) groups; or 1-2independently selected R^(c) groups; or 1-2 independently selected R^(d)groups; or 1-2 independently selected R^(e) groups; or 1-2 independentlyselected R^(f) groups; or 1-2 independently selected R^(g) groups Insome embodiments, R^(g) is 4-pyrimidinyl optionally substituted withfrom 1-3 R^(e).

In some embodiments of compounds of formula (I), Z is 2-pyridyl,3-pyridyl, 4-pyridyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,1H-pyrrolo[2,3-b]pyridine-5-yl, 1H-pyrrolo[2,3-b]pyridine-6-yl,1H-pyrrolo[2,3-b]pyridine-4-yl, 1H-pyrrolo[2,3-b]pyridine-3-yl,1H-pyrrolo[2,3-b]pyridine-2-yl, 1H-pyrrolo[2,3-b]pyridine-1-yl,1H-pyrazolo[5,4-b]pyridine-4-yl, 1H-pyrazolo[5,4-b]pyridine-5-yl,1H-pyrazolo[5,4-b]pyridine-6-yl, 1H-pyrazolo[5,4-d]pyrimidin-3-yl,1H-pyrazolo[5,4-d]pyrimidin-1-yl, 1H-indazol-4-yl, 1H-indazol-5-yl,1H-indazol-6-yl, 1H-indazol-7-yl, quinazolin-5-yl, quinazolin-6-yl,7-oxo-8H-pyrido[2,3-d]pyrimidin-5-yl,7-oxo-8H-pyrido[2,3-d]pyrimidin-6-yl, each of which is optionallysubstituted, for example, each of which is optionally substituted withfrom 1 to 3 independently selected R⁷ substituents; or 1 to 3independently selected R^(a) substituents; or 1 to 3 independentlyselected R^(b) substituents; or 1 to 3 independently selected R^(c)substituents; or 1 to 3 independently selected R^(d) substituents; or 1to 3 independently selected R^(e) substituents; 1 to 3 independentlyselected R^(f) substituents; or 1 to 3 independently selected R^(g)substituents. In some instances, R^(g) is further optionally substitutedwith 1-3 R^(e) groups.

In some embodiments of the compounds of formula (I), Z is an optionallysubstituted heteroaryl having the formula:

Y¹ and Y⁵ are each independently C or N; Y², Y³ and Y⁴ are eachindependently a carbon atom or a heteroatom selected from O, N or S,wherein N and S are optionally oxidized; G is an optionally substitutedheteroaryl; and

is a single bond or a double bond to maintain Z being aromatic, with theproviso that Y¹, Y², Y³, Y⁴ and Y⁵ are not simultaneously an optionallysubstituted carbon; the wavy line indicates the point of attachment tothe rest of the molecule. In one embodiment, G is halogen. In someinstances, G is an optionally substituted 6-membered heteroaryl. Inother instances, G is a pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl,each of which is optionally substituted. In some embodiments, G is apyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, each of which isoptionally substituted with from 1-2 independently selected R⁷ groups;or 1-2 independently selected R^(a) groups; or 1-2 independentlyselected R^(b) groups; or 1-2 independently selected R^(c) groups; or1-2 independently selected R^(d) groups; or 1-2 independently selectedR^(e) groups; or 1-2 independently selected R^(f) groups; or 1-2independently selected R^(g) groups. In one instance, G is an optionallysubstituted 4-pyrimidinyl. In another instance, G is an optionallysubstituted 2-amino-4-pyrimidinyl. In another instance, G is4-pyrimidinyl optionally substituted with from 1-2 independentlyselected R⁷ groups; or 1-2 independently selected R^(a) groups; or 1-2independently selected R^(b) groups; or 1-2 independently selected R^(c)groups; or 1-2 independently selected R^(d) groups; or 1-2 independentlyselected R^(e) groups; or 1-2 independently selected R^(f) groups; or1-2 independently selected R^(g) groups. In another instance, G is2-amino-4-pyrimidinyl optionally substituted with from 1-2 independentlyselected R⁷ groups; or 1-2 independently selected R^(a) groups; or 1-2independently selected R^(b) groups; or 1-2 independently selected R^(c)groups; or 1-2 independently selected R^(d) groups; or 1-2 independentlyselected R^(e) groups; or 1-2 independently selected R^(f) groups; or1-2 independently selected R^(g) groups. In some embodiments, G isheteroaryl substituted with —OCH₃, —NH₂ or —NH[CH₂CH(CH₃)NHC(O)OCH₃].

In some embodiments of the compounds of formula (I), G is selected from3-pyridyl, 4-pyrimidinyl, 2-amino-4-pyrimidinyl,2-methoxy-4-pyrimidinyl,

each of which is optionally substituted with from 1-2 independentlyselected R⁷ groups; or 1-2 independently selected R^(a) groups; or 1-2independently selected R^(b) groups; or 1-2 independently selected R^(c)groups; or 1-2 independently selected R^(d) groups; or 1-2 independentlyselected R^(e) groups; or 1-2 independently selected R^(f) groups; or1-2 independently selected R^(g) groups.

In some embodiments of the compounds of formula (I), Z is

which is optionally substituted with from 1 to 3 independently selectedR⁷ substituents; or 1 to 3 independently selected R^(a) substituents; or1 to 3 independently selected R^(b) substituents; or 1 to 3independently selected R^(c) substituents; or 1 to 3 independentlyselected R^(d) substituents; or 1 to 3 independently selected R^(e)substituents; 1 to 3 independently selected R^(f) substituents; or 1 to3 independently selected R^(g) substituents selected from F, Cl, Br, I,—CN, —OH, —CF₃, NH₂, CF₃O—, CH₃—, ethyl, propyl, isopropyl, CH₃O, —NO₂,t-butyl, cyclopropyl, cyclopropylmethyl, cyclopropylamino, pyrimidinyl,4-pyrimidinyl, cyclopropylmethylamino, 1-cyanocyclopropyl, methylamino,dimethylamino, methylthio, acetoxy, acetyl, methoxycarbonyl, acetamido,1-cyclopropylethyl, 2-cyclopropylethyl, 1-cyclopropylethylamino,2-cyclopropylethylamino, 1-hydroxy-1-methylethyl, methylcarbamoyl,1-carboxycyclopropyl, 1-carbamoylcyclopropyl,1-methoxycarbonylcyclopropyl, 1-cyanoisopropyl, 1-hydroxycyclopropyl,1-hydoxyisopropyl, cyclobutoxy, cyclopentoxy, cycloheyloxy,4-morpholino, 4-hydroxypiperidinyl, 1-piperidinyl, piperazinyl,4-methylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, azetidinyl,pyrrolidinyl, cyclopropylcarbamoyl, 5-methyl-1,2,4-oxadiazol-3-yl,5-methyl-1,3,4-oxadiazol-2yl, 5-dimethylamino-1,3,4-oxadiazol-2yl,2-(methoxycarbonylamino)propyl or 5-methylamino-1,3,4-thiadiazol-2-yl.In some instances, R^(g) is optionally substituted with 1-3 R^(e)groups. Y¹, Y², Y³, Y⁴, Y⁵ and G are as defined in any of theembodiments disclosed herein.

In some embodiments of the compounds of formula (I), Z is

each of which is optionally substituted with from 1 to 3 independentlyselected R⁷ substituents; or 1 to 3 independently selected R^(a)substituents; or 1 to 3 independently selected R^(b) substituents; or 1to 3 independently selected R^(c) substituents; or 1 to 3 independentlyselected R^(d) substituents; or 1 to 3 independently selected R^(e)substituents; 1 to 3 independently selected R^(f) substituents; or 1 to3 independently selected R^(g) substituents, wherein the R^(g) group isoptionally further substituted with 1-3 R^(e). In one embodiment, G is4-pyrimidinyl optionally substituted with from 1-2 independentlyselected R⁷ groups; or 1-2 independently selected R^(a) groups; or 1-2independently selected R^(b) groups; or 1-2 independently selected R^(c)groups; or 1-2 independently selected R^(d) groups; or 1-2 independentlyselected R^(e) groups; or 1-2 independently selected R^(f) groups; or1-2 independently selected R^(g) groups. In another embodiment, G is2-amino-4-pyrimidinyl optionally substituted with from 1-2 independentlyselected R⁷ groups; or 1-2 independently selected R^(a) groups; or 1-2independently selected R^(b) groups; or 1-2 independently selected R^(c)groups; or 1-2 independently selected R^(d) groups; or 1-2 independentlyselected R^(e) groups; or 1-2 independently selected R^(f) groups; or1-2 independently selected R^(g) groups.

In some embodiments of compounds of formula (I), Z is

each of which is optionally substituted, for example, with from 1 to 3independently selected R⁷ substituents; or 1 to 3 independently selectedR^(a) substituents; or 1 to 3 independently selected R^(b) substituents;or 1 to 3 independently selected R^(c) substituents; or 1 to 3independently selected R^(d) substituents; or 1 to 3 independentlyselected R^(e) substituents; 1 to 3 independently selected R^(f)substituents; or 1 to 3 independently selected R^(g) substituents,wherein the R^(g) group is optionally further substituted with 1-3R^(e).

In some embodiments of compounds of formula (I), Y is as defined in theSummary. All the other variables of formula (I) and Z, L, R³ and R⁴ areas defined in any of the embodiments of compounds of formula (I) asdescribed herein.

In some embodiments of compounds of formula (I), Y is —N(R¹)(R²) or—C(R⁸)(R⁹)(R¹⁰), wherein R¹ and R² are each independently selected fromthe group consisting of optionally substituted C₁₋₆alkyl, optionallysubstituted C₃₋₈cycloalkyl, optionally substituted C₃₋₈cycloalkylalkyl,optionally substituted heterocycloalkyl, optionally substitutedheterocycloalkylalkyl, optionally substituted aryl, optionallysubstituted arylalkyl, optionally substituted heteroaryl and optionallysubstituted heteroarylalkyl; or R¹ and R² taken together with thenitrogen atom to which they are attached form an optionally substitutedfour to eight-membered ring having from 0-2 additional heteroatoms asring members selected from N, O or S, wherein N and S are optionallyoxidized, wherein the four to eight-membered ring is optionallysubstituted with from one to three groups independently selected fromhalogen, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl, C₃₋₈ cycloalkyl,C₃₋₈ cycloalkylalkyl, aryl, arylalkyl or R^(e). R⁸, R⁹ and R¹⁰ are eachindependently H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₃₋₈cycloalkyl, C₃₋₈ cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl or —X¹R⁵; wherein X¹is —NR⁶, O or S; R⁶ is H, C₁₋₆ alkyl or aryl; and R⁵ is H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkylalkyl,aryl, arylalkyl, heteroaryl or heteroarylalkyl, wherein R⁵ is optionallysubstituted with from 1 to 3 R^(e) substituents, wherein the aliphaticor aromatic portion of R⁸, R⁹ and R¹⁰ are each optionally substitutedwith from 1 to 3 members independently selected from the groupconsisting of C₃₋₈cycloalkyl, C₃₋₈cycloalkylalkyl, aryl, arylalkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl andR^(e); or any two of the R⁸, R⁹ and R¹⁰ groups taken together with thecarbon atom to which they are attached form a 3 to 8-memberedcarbocyclic ring or a 4 to 8-membered heterocyclic ring having from 1 to2 heteroatoms as ring members selected from N, O or S, wherein the 3 to8-membered carbocyclic ring or the 4 to 8-membered heterocyclic ring isoptionally substituted with from one to three groups independentlyselected from C₁₋₆haloalkyl, C₁₋₆haloalkoxy, C₁₋₆alkyl, C₃₋₈cycloalkyl,C₃₋₈cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl orR^(e), provided at each occurrence, at least two of the R⁸, R⁹ and R¹⁰groups are not simultaneously hydrogen. All the other variables Z, L, R³and R⁴ of formula (I) are as defined in any of the embodiments describedherein.

In some embodiments of compounds of formula (I), Y is —N(R¹)(R²),wherein R¹ and R² are each independently selected from C₁₋₆alkyl,C₃₋₈cycloalkyl, C₃₋₈cycloalkylalkyl, aryl, aryl-C₁₋₄alkyl, heteroaryl orheteroaryl-C₁₋₄alkyl, each of which is optionally substituted with from(i) 1-3 substituents independently selected from C₁₋₆alkoxy,C₁₋₆haloalkyl, C₁₋₆haloalkoxy, C₁₋₆alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl or R^(e);or (ii) 1, 2 or 3 independently selected R^(a) substituents; or (iii) 1,2 or 3 independently selected R^(b) substituents; or (iv) 1, 2 or 3independently selected R^(c) substituents; or (v) 1, 2 or 3independently selected R^(d) substituents; or (vi) 1, 2 or 3independently selected R^(f) groups. All the other variables Z, L, R³and R⁴ of formula (I) are as defined in any of the embodiments describedherein.

In some embodiments of compounds of formula (I), R¹ is —CH₃ and R² isC₂₋₆alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkylalkyl, aryl, aryl-C₁₋₄alkyl,heteroaryl or heteroaryl-C₁₋₄alkyl, each of which is optionallysubstituted with from (i) 1-3 substituents independently selected fromC₁₋₆alkoxy, C₁₋₆haloalkyl, C₁₋₆haloalkoxy, C₁₋₆alkyl, C₃₋₈cycloalkyl,C₃₋₈cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl orR^(e); or (ii) 1, 2 or 3 R^(a) substituents; or (iii) 1, 2 or 3 R^(b)substituents; or (iv) 1, 2 or 3 R^(c) substituents; or (v) 1, 2 or 3R^(d) substituents; or (vi) 1, 2 or 3 R^(f) groups. In certaininstances, R′ is —CH₃ and R² is C₂₋₆alkyl. All the other variables Z, L,R³ and R⁴ of formula (I) are as defined in any of the embodimentsdescribed herein.

In some embodiments of compounds of formula (I), R¹ and R² are eachindependently selected from C₁₋₆alkyl, C₃₋₈cycloalkyl,C₃₋₈cycloalkylalkyl, aryl, aryl-C₁₋₄alkyl, heteroaryl orheteroaryl-C₁₋₄alkyl, each of which is optionally substituted with from1, 2 or 3 R^(h) members selected from F, Cl, Br, I, —CN, —OH, —CF₃, NH₂,CF₃O—, CH₃—, CH₃O, —NO₂, cyclopropyl, cyclopropylmethyl,cyclopropylamino, cyclopropylmethylamino, 1-cyanocyclopropyl,methylamino, dimethylamino, methylthio, acetoxy, acetyl,methoxycarbonyl, acetamido, methylcarbamoyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl,2-oxetanyl, 3-oxtetanyl, 2-oxetanylmethyl, 3-oxtetanylmethyl,2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrofuranylmethyl,3-tetrahydrofuranylmethyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,4-morpholinyl, 2-morpholinyl or 3-morpholinyl. In certain instances,R^(h) is F, Cl, —CN, —OH, —CF₃, NH₂, CF₃O—, CH₃—, CH₃O, —NO₂,cyclopropyl, cyclopropylmethyl, cyclopropylamino,cyclopropylmethylamino, 1-cyanocyclopropyl, methylamino, dimethylamino,methylthio, acetoxy, acetyl, methoxycarbonyl, acetamido,methylcarbamoyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridylmethyl,3-pyridylmethyl, 4-pyridylmethyl, 2-oxetanyl, 3-oxtetanyl,2-oxetanylmethyl, 3-oxtetanylmethyl, 2-tetrahydrofuranyl,3-tetrahydrofuranyl, 2-tetrahydrofuranylmethyl,3-tetrahydrofuranylmethyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,4-morpholinyl, 2-morpholinyl or 3-morpholinyl. In one embodiment, R^(h)is halogen. All the other variables Z, L, R³ and R⁴ of formula (I) areas defined in any of the embodiments described herein.

In some embodiments of compounds of formula (I), R¹ is —CH₃ and R² isC₂₋₆alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkylalkyl, aryl, aryl-C₁₋₄alkyl,heteroaryl or heteroaryl-C₁₋₄alkyl, each of which is optionallysubstituted with from 1, 2 or 3 R^(h) members selected from F, Cl, Br,I, —CN, —OH, —CF₃, NH₂, CF₃O—, CH₃—, CH₃O, —NO₂, cyclopropyl,cyclopropylmethyl, cyclopropylamino, cyclopropylmethylamino,1-cyanocyclopropyl, methylamino, dimethylamino, methylthio, acetoxy,acetyl, methoxycarbonyl, acetamido, methylcarbamoyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl,2-oxetanyl, 3-oxtetanyl, 2-oxetanylmethyl, 3-oxtetanylmethyl,2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrofuranylmethyl,3-tetrahydrofuranylmethyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,4-morpholinyl, 2-morpholinyl or 3-morpholinyl. In certain instances,R^(h) is F, Cl, —CN, —OH, —CF₃, NH₂, CF₃O—, CH₃—, CH₃O, —NO₂,cyclopropyl, cyclopropylmethyl, cyclopropylamino,cyclopropylmethylamino, 1-cyanocyclopropyl, methylamino, dimethylamino,methylthio, acetoxy, acetyl, methoxycarbonyl, acetamido,methylcarbamoyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridylmethyl,3-pyridylmethyl, 4-pyridylmethyl, 2-oxetanyl, 3-oxtetanyl,2-oxetanylmethyl, 3-oxtetanylmethyl, 2-tetrahydrofuranyl,3-tetrahydrofuranyl, 2-tetrahydrofuranylmethyl,3-tetrahydrofuranylmethyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,4-morpholinyl, 2-morpholinyl or 3-morpholinyl. All the other variablesZ, L, R³ and R⁴ of formula (I) are as defined in any of the embodimentsdescribed herein.

In some embodiments of compounds of formula (I), R¹ is —CH₃ and R² isselected from ethyl, propyl, butyl, pentyl, cyclopropyl,cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl,cyclopentylmethyl, cyclohexyl, cyclohexylmethyl, phenyl or benzyl, eachof which is optionally substituted with from 1-3 substituentsindependently selected from F, Cl, —CN, —OH, —CF₃, NH₂, CF₃O—, CH₃—,CH₃O, —NO₂, cyclopropyl, cyclopropylmethyl, cyclopropylamino,cyclopropylmethylamino, 1-cyanocyclopropyl, methylamino, dimethylamino,methylthio, acetoxy, acetyl, methoxycarbonyl, acetamido,methylcarbamoyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridylmethyl,3-pyridylmethyl, 4-pyridylmethyl, 2-oxetanyl, 3-oxtetanyl,2-oxetanylmethyl, 3-oxtetanylmethyl, 2-tetrahydrofuranyl,3-tetrahydrofuranyl, 2-tetrahydrofuranylmethyl,3-tetrahydrofuranylmethyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,4-morpholinyl, 2-morpholinyl or 3-morpholinyl. All the other variablesZ, L, R³ and R⁴ of formula (I) are as defined in any of the embodimentsdescribed herein.

In some embodiments of compounds of formula (I), Y is —N(R¹)(R²),wherein R¹ and R² taken together with the nitrogen to which they attachform an optionally substituted 5- or 6-membered heterocycloalkyl ringhaving from 0-1 additional heteroatoms as ring members selected from O,N or S, wherein N or S is optionally oxidized. In some embodiments, R¹and R² taken together with the nitrogen to which they attach form a5-membered heterocycloalkyl having from 0-1 additional heteroatoms asring members selected from O, N or S, wherein the 5-memberedheterocycloalkyl is optionally substituted with from 1-2 independentlyselected R⁷ groups; or 1-2 independently selected R^(a) groups; or 1-2independently selected R^(b) groups; or 1-2 independently selected R^(c)groups; or 1-2 independently selected R^(d) groups; or 1-2 independentlyselected R^(e) groups; or 1-2 independently selected R^(f) groups; or1-2 independently selected R^(g) groups. In other embodiments, R¹ and R²taken together with the nitrogen to which they attach form a 6-memberedheterocycloalkyl having from 0-1 additional heteroatoms as ring membersselected from O, N or S, wherein the 6-membered heterocycloalkyl isoptionally substituted with from 1-2 independently selected R⁷ groups;or 1-2 independently selected R^(a) groups; or 1-2 independentlyselected R^(b) groups; or 1-2 independently selected R^(c) groups; or1-2 independently selected R^(d) groups; or 1-2 independently selectedR^(e) groups; or 1-2 independently selected R^(f) groups; or 1-2independently selected R^(g) groups.

In some embodiments of compounds of formula (I), Y is —N(R¹)(R²),wherein —N(R¹)(R²) is selected from 1-azetindinyl, 1-pyrrolidinyl,1-piperidinyl, 4-morpholinyl, 4-thiomorpholinyl, 3-oxazolidinyl,3-thiazolidinyl, 2-isoxazolidinyl, 2-isothiazolidinyl, 1-pyrazolidinyl,1-piperazinyl, 1-hexahydropyrimidinyl or 1-hexahydropyridazinyl, each ofwhich is (i) optionally substituted with from 1 to 3 R¹¹ substituentsindependently selected from the group consisting of halogen, C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆haloalkyl, C₁₋₆haloalkoxy, C₁₋₆alkyl, C₃₋₈cycloalkyl,C₃₋₈cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl and R^(c); or (ii) two adjacentR¹¹ substituents together with the atom to which they are attached forma 5 or 6-membered aromatic ring having from 0 to 2 additional atoms asring members selected from O, N or S or (iii) optionally substitutedwith from 1 to 8 deuteriums with at least 52.5%, 60%, 70%, 75%, 80%,90%, 95%, 99%, 99.5% or 99.9% deuterium incorporation for eachdeuterium. In certain instances, R¹¹ is F, Cl, Br, I, —CN, —OH, —CF₃,NH₂, CF₃O—, CH₃—, CH₃O, —NO₂, cyclopropyl, cyclopropylmethyl,cyclopropylamino, cyclopropylmethylamino, 1-cyanocyclopropyl,methylamino, dimethylamino, methylthio, acetoxy, acetyl,methoxycarbonyl, acetamido, methylcarbamoyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl,2-oxetanyl, 3-oxtetanyl, 2-oxetanylmethyl, 3-oxtetanylmethyl,2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrofuranylmethyl,3-tetrahydrofuranylmethyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,4-morpholinyl, 2-morpholinyl or 3-morpholinyl. In other instances, R¹¹is F, Cl, —CN, —OH, —CF₃, NH₂, CF₃O—, CH₃—, CH₃O, —NO₂, cyclopropyl,cyclopropylmethyl, cyclopropylamino, cyclopropylmethylamino,1-cyanocyclopropyl, methylamino, dimethylamino, methylthio, acetoxy,acetyl, methoxycarbonyl, acetamido, methylcarbamoyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl,2-oxetanyl, 3-oxtetanyl, 2-oxetanylmethyl, 3-oxtetanylmethyl,2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrofuranylmethyl,3-tetrahydrofuranylmethyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,4-morpholinyl, 2-morpholinyl or 3-morpholinyl. In other instances, R¹¹is F, CH₃, methoxycarbonyl, ethoxycarbonyl, —CH₃, CH₃(CO)NH—, vinyl,propen-3-yl or CH₃(CO)(CH₃)N—. In some embodiments, each hydrogen atomin Y is optionally replaced by a deuterium atom with at least 52.5%,60%, 70%, 75%, 80%, 90%, 95%, 99%, 99.5% or 99.9% deuteriumincorporation for each deuterium. In certain embodiments, Y is1-azetindinyl, 1-pyrrolidinyl, 1-piperidinyl or 1-piperazinyl, each ofwhich is optionally substituted with from 1-3 independently selected R¹¹groups. All the other variables Z, L, R³ and R⁴ of formula (I) are asdefined in any of the embodiments described herein.

In some embodiments of compounds of formula (I), Y is —C(R⁸)(R⁹)(R¹⁰),where R⁸ is H and R⁹ and R¹⁰ are each independently C₁₋₆alkyl,optionally substituted with from 1 to 3 R^(d) or 1-3 R^(e) groups. Insome embodiments, R⁸, R⁹ and R¹⁰ are each independently C₁₋₆alkyl,optionally substituted with from 1 to 3 R^(d) or 1-3 R^(e). In someembodiments, —C(R⁸)(R⁹)(R¹⁰) is cyclopropyl, cyclobutyl, cyclohexyl,cyclopentyl, cycloheptyl, cyclooctyl, each of which is optionallysubstituted with from 1-3 R¹² substituents independently selected fromF, Cl, Br, I, —CN, —OH, —CF₃, NH₂, CF₃O—, CH₃—, CH₃O, —CH₂CH═CH₂, —NO₂,cyclopropyl, cyclopropylmethyl, cyclopropylamino,cyclopropylmethylamino, 1-cyanocyclopropyl, vinyl, methylamino,dimethylamino, methylthio, acetoxy, acetyl, methoxycarbonyl, acetamido,methylcarbamoyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridylmethyl,3-pyridylmethyl, 4-pyridylmethyl, 2-oxetanyl, 3-oxtetanyl,2-oxetanylmethyl, 3-oxtetanylmethyl, 2-tetrahydrofuranyl,3-tetrahydrofuranyl, 2-tetrahydrofuranylmethyl,3-tetrahydrofuranylmethyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,4-morpholinyl, 2-morpholinyl or 3-morpholinyl. In some instances, R¹² isF, —CN, —OH, —CF₃, NH₂, CF₃O—, CH₃—, CH₃O, —NO₂, cyclopropyl,cyclopropylmethyl, cyclopropylamino, cyclopropylmethylamino,1-cyanocyclopropyl, methylamino, dimethylamino, methylthio, acetoxy,acetyl, methoxycarbonyl, acetamido, methylcarbamoyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl,2-oxetanyl, 3-oxtetanyl, 2-oxetanylmethyl, 3-oxtetanylmethyl,2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrofuranylmethyl,3-tetrahydrofuranylmethyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,4-morpholinyl, 2-morpholinyl or 3-morpholinyl. In some embodiments,—C(R⁸)(R⁹)(R¹⁰) is 2-azetindinyl, 3-azetindinyl, 3-pyrrolidinyl,2-pyrrolidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl,2-morpholinyl, 3-morpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl,2-oxazolidinyl, 4-oxazolidinyl, 5-oxazolidinyl, 2-thiazolidinyl,4-thiazolidinyl, 5-thiazolidinyl, 3-isoxazolidinyl, 4-isoxazolidinyl,5-isoxazolidinyl, 3-isothiazolidinyl, 4-isothiazolidinyl,5-isothiazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, 2-piperazinyl,2-hexahydropyrimidinyl, 4-hexahydropyrimidinyl, 5-hexahydropyrimidinyl,3-hexahydropyridazinyl or 4-hexahydropyridazinyl, each of which isoptionally substituted with 1 to 3 R¹² substituents. In certainembodiments, —C(R⁸)(R⁹)(R¹⁰) is cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl, each of which is optionally substituted with 1 to 3 R¹²substituents. In some embodiments, each hydrogen atom in Y is optionallyreplaced by a deuterium atom with at least 52.5%, 60%, 70%, 75%, 80%,90%, 95%, 99%, 99.5% or 99.9% deuterium incorporation for eachdeuterium. All the other variables Z, L, R³ and R⁴ of formula (I) are asdefined in any of the embodiments described herein.

In some embodiments of compounds of formula (I), Y is 1-piperazinyl,1-pyrrolidinyl, 2-oxo-1-pyrrolidinyl, 3-oxo-1-pyrrolidinyl1-piperidinyl, 4-morpholino or 4-thiomorpholino, each of which isoptionally substituted. In some embodiments of compounds of formula (I),is Y is selected from the group consisting of cyclopropyl, cyclobutyl,cyclohexyl, cyclopentyl, cycloheptyl, cyclooctyl, 1-azetindinyl,1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, 4-thiomorpholinyl3-oxazolidinyl, 3-thiazolidinyl, 2-isoxazolidinyl, 2-isothiazolidinyl,1-pyrazolidinyl, 1-piperazinyl, 1-hexahydropyrimidinyl,1-hexahydropyridazinyl, (CH₃)(CF₃CH₂)N—, cycloproyplmethylamino,sec-butyl, pentan-2-yl and pentan-3-yl, each of which is (i) optionallysubstituted with from one to three R¹³ substituents independentlyselected from the group consisting of halogen, C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆haloalkyl, C₁₋₆haloalkoxy, C₁₋₆alkyl, C₃₋₈ cycloalkyl, C₃₋₈cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl and R^(c); or (ii) two adjacentR¹³ substituents together with the atom to which they are attached forma 5 or 6-membered aromatic ring having from 0 to 2 additional atoms asring members selected from O, N or S; or (iii) optionally substitutedwith from 1 to 11 deuteriums having at least 52.5%, 60%, 70%, 75%, 80%,90%, 95%, 99%, 99.5% or 99.9% deuterium incorporation for eachdeuterium. In one embodiment, Y is cyclopropyl optionally substitutedwith 1 to 2 R¹³ groups. In another embodiment, Y is cyclopentyloptionally substituted with 1 to 2 R¹³ groups. In yet another embodimentY is 1-pyrrolidinyl optionally substituted with 1 to 2 R¹³ groups. Inother embodiment, Y is 1-piperidinyl optionally substituted with 1 to 2R¹³ groups. In another embodiment, Y is 1-pyrrolidinyl,3-fluoro-1-pyrrolidinyl, (3S)-3-fluoro-1-pyrrolidinyl,(3R)-3-fluoro-1-pyrrolidinyl, 3,3-difluoro-1-pyrrolidinyl,3-C₁₋₆alkyl-C(O)—C₁₋₆alkyl-N-1-pyrrolidinyl,3-C₁₋₆alkyl-C(O)NH-1-pyrrolidinyl, C₁₋₆alkoxycarbonyl-1-pyrrolidinyl or3,3-dimethyl-1-pyrrolidinyl. In certain instances, R¹³ is F, Cl, Br, I,—CN, —OH, —CF₃, NH₂, CF₃O—, CH₃—, CH₃O, —NO₂, cyclopropyl,cyclopropylmethyl, cyclopropylamino, cyclopropylmethylamino,1-cyanocyclopropyl, methylamino, dimethylamino, methylthio, acetoxy,acetyl, methoxycarbonyl, acetamido, methylcarbamoyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl,2-oxetanyl, 3-oxtetanyl, 2-oxetanylmethyl, 3-oxtetanylmethyl,2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrofuranylmethyl,3-tetrahydrofuranylmethyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,4-morpholinyl, 2-morpholinyl or 3-morpholinyl. In one instance, R¹³ is—F, methoxycarbonyl, ethoxycarbonyl, —CH₃, CH₃(CO)NH—, vinyl,propen-3-yl or CH₃(CO)(CH₃)N—. In another instance, R¹³ is —F,methoxycarbonyl, ethoxycarbonyl, —CH₃, CH₃(CO)NH— or CH₃(CO)(CH₃)N—. Inyet another instance, R¹³ is vinyl or propen-3-yl. All the othervariables Z, L, R³ and R⁴ of formula (I) are as defined in any of theembodiments described herein.

In some embodiments of compounds of formula (I), L is a bond, —C(O)—,—C(S)—, —C(O)NH—, —NHC(O)— or optionally substituted —C(═CH₂)—, whereintwo substituents attached to the same methylene carbon in the —C(═CH₂)—group are optionally taken together to form an optionally substituted 5-or 6-membered ring having from 0-4 heteroatoms selected from O, N or S,where N and S are optionally oxidized. In certain embodiments, L is abond, —C(O)—, —C(O)NH— or —NHC(O)—. In certain instances, L is—C(—C═CH₂)—, optionally substituted with from 1-2 R^(c); or 1-2 R^(e)substituents. In some instances, L is —C[═C(R¹⁴)(R¹⁵)]—, wherein R¹⁴ andR¹⁵ are taken together with the carbon atom to which they attach form 5-or 6-membered ring having from 0-4 heteroatoms selected from O, N or S,where N and S are optionally oxidized. In some embodiments, L is a bond.In other embodiments, L is —C(O)—. In yet other embodiments, L is—C(O)NH— or —NHC(O)—. All the other variables Z, Y, R³ and R⁴ of formula(I) are as defined in any of the embodiments described herein.

In some embodiments of compounds of formula (I), R³ is H. In certainembodiments, R³ is C₁₋₆alkyl. All the other variables Z, Y, L and R⁴ offormula (I) are as defined in any of the embodiments described herein.

In some embodiments of compounds of formula (I), R⁴ is halogen,hydrogen, C₁₋₂alkyl, C₁₋₂haloalkyl, CN, C₁₋₂haloalkoxy or C₁₋₂alkoxy. Inone instance, R⁴ of formula (I) is attached to the phenyl ring at themeta position with respect to the fluoro substituent. In anotherinstance, R⁴ of formula (I) is attached to the phenyl ring at the paraposition with respect to the fluoro substituent. In certain embodiments,R⁴ is H, F, Cl, CH₃, —CH₂CH₃, —OCH₃, —CF₃, —CHF₂, —CH₂F, CN, —OCF₃,—OCHF₂ or —OCH₂F. In one embodiment, R⁴ is F. In another embodiment, R⁴is Cl. In yet another embodiment, R⁴ is H. In another embodiment, R⁴ isCH₃. All the other variables Z, Y, R³ and L of formula (I) are asdefined in any of the embodiments described herein.

In some embodiments, the disclosure provides a compound of formula (I′):

Z, Y and R³ are as defined in any of the embodiments of compounds offormula (I) or subgeneric formulas of formula (I). In one embodiment, Yis —N(R¹)(R²). In another embodiment, Y is —C(R⁸)(R⁹)(R¹⁰), where R¹,R², R⁸, R⁹ and R¹⁰ are as defined in any of embodiments of formula (I)or subgeneric formulas of formula (I) as described herein. L¹ and L² areeach independently a bond, —C(O)—, —C(S)—, —C(O)NH—, —NHC(O)— oroptionally substituted —C(═CH₂)—, wherein two substituents attached tothe same methylene carbon in the —C(═CH₂)— group are optionally takentogether to form an optionally substituted 5- or 6-membered ring havingfrom 0-4 heteroatoms selected from O, N or S, where N and S areoptionally oxidized. E is an optionally substituted aryl or optionallysubstituted 5- or 6-membered heteroaryl. In some instances, E is an arylor 5- or 6-membered heteroaryl, each of which is optionally substitutedwith from 1 to 3 independently selected R⁷ substituents; or 1-3independently selected R^(a) substituents; or 1-3 independently selectedR^(b) substituents; or 1-3 independently selected R^(c) substituents; or1-3 independently selected R^(d) substituents; or 1-3 independentlyselected R^(e) substituents; or 1-3 independently selected R^(f)substituents; or 1-3 independently selected R^(g) substituents; or 1-3independently selected halogens. In certain instances, when L² is a bondand E is

then Z is other than a 5-position optionally substituted

core, wherein the single wavy line in

indicates the attachment to —N(R³)SO₂Y group and the double wavy line in

indicates the attachment to E, wherein the wavy line in

indicates the attachment to L¹ and wherein R⁴ is H or F. In certainembodiments, when L² is a bond and E is

then Z is other than an optionally substituted

core.Subformulas

In one group of embodiments, compounds of formula (I) have subformula(Ia):

Y is —N(R¹)(R²) or —C(R⁸)(R⁹)(R¹⁰). R⁴ is H, F, CH₃ or Cl. In oneinstance, R⁴ is H. In another instance, R⁴ is F. The variables R¹, R²,R³, R⁴, Y, Z, R⁸, R⁹, R¹⁰, and L are as defined in formula (I) and anyembodiments as described herein.

In a second group of embodiments, compounds of formula (I) or (Ia) havesubformulas (Ia-1) or (Ia-2):

The variables R¹, R², R³, R⁴, R⁸, R⁹, R¹⁰, Z and L are as defined informulas (I) or (Ia) and any embodiments as described herein.

In a third group of embodiments, compounds of formula (I) havesubformula (Ib):

Y is —N(R¹)(R²) or —C(R⁸)(R⁹)(R¹⁰). R⁴ is F, CH₃, CN, CF₃ or Cl. In oneinstance, R⁴ is F. In another instance, R⁴ is Cl. In yet anotherinstance, R⁴ is CH₃. In some embodiments, R³ is H and L is a bond or—C(O)—. Other variables Y, R¹, R², R³, R⁸, R⁹, R¹⁰, Z and L are asdefined in formula (I) and any embodiments as described herein.

In a fourth group of embodiments, compounds of formula (I) or (Ib) havesubformulas (Ib-1) or (Ib-2):

In some embodiments, R³ is H. In one embodiment, L is —C(O)—. In anotherembodiment, R⁴ is F, Cl, CH₃, CN or CF₃. In certain embodiments ofcompounds of formula (Ib-1) or (Ib-2), Z is an optionally substituted1H-pyrrolo[2,3-b]pyridine-3-yl. The variables R¹, R², R³, R⁴, R⁸, R⁹,R¹⁰, Z and L are as defined in formula (I) and any embodiments asdescribed herein.

In a fifth group embodiments, compounds of formulas (I), (Ib) or (Ib-1)have subformula (Ib-1a):

Q¹ is CN, halogen, —OH, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₁₋₆ alkoxy, optionally substituted C₃₋₆cycloalkyl,optionally substituted C₁₋₆ haloalkyl, optionally substituted C₁₋₆haloalkoxy, optionally substituted aryl and optionally substitutedheteroaryl; optionally wherein two adjacent substituents on asubstituted aryl or a substituted heteroaryl ring together with theatoms to which they are attached form an optionally substituted 5- or6-membered ring having from 0 to 3 additional heteroatoms selected fromN, O or S. Q² is H, halogen, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, aryl, arylalkyl, heteroaryl,heteroarylalkyl, C₃₋₈ cycloalkyl-C₀₋₄ alkyl or (R¹⁷)(R¹⁸)N—, wherein R¹⁷and R¹⁸ are each independently selected from the group consisting of H,C₁₋₆ alkyl, C₁₋₆ alkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl,C₃₋₈ cycloalkyl-C₀₋₄ alkyl, heterocycloalkyl and heterocycloalkyl-C₁₋₄alkyl; or R¹⁷ and R¹⁸ taken together with the nitrogen atom to whichthey are attached form a four to eight-membered ring having from 0-2additional heteroatoms as ring members selected from N, O or S; whereinQ² is optionally substituted with from one to three groups independentlyselected from R^(e). In some embodiments, Q¹ is CN, halogen, —OH, C₁₋₆alkyl, C₁₋₆ alkoxy, C₃₋₆cycloalkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,aryl or heteroaryl, wherein the aliphatic or aromatic portion of Q¹ iseach independently optionally substituted with from 1-5 independentlyselected R⁷; or 1 to 5 independently selected R^(a) substituents; or 1to 5 independently selected R^(b) substituents; or 1 to 5 independentlyselected R^(c) substituents; or 1 to 5 independently selected R^(d)substituents; or 1 to 5 independently selected R^(e) substituents; 1 to5 independently selected R^(f) substituents; or 1 to 5 independentlyselected R^(g) substituents. In some embodiments, Q² is H, F, Cl, I, CN,CH₃, CH₃O—, cyclopropylamino or cyclopropylmethylamino. In otherembodiments, Q² is H. In some embodiments, R³ is H. In otherembodiments, R⁴ is F, Cl, CH₃, CN or CF₃. In other embodiments, R⁴ is For Cl. In one embodiment, R⁴ is F. The variables R¹, R², R³ and R⁴ areas defined in formula (I) and any embodiments as described herein.

In some embodiments of compounds of formula (Ib-1a), Q¹ is phenyl,1-naphthyl or 2-naphthyl, each of which is optionally substituted withfrom 1 to 3 independently selected R⁷ substituents; 1 to 3 independentlyselected R^(a) substituents; or 1 to 3 independently selected R^(b)substituents; or 1 to 3 independently selected R^(c) substituents; or 1to 3 independently selected R^(d) substituents; or 1 to 3 independentlyselected R^(e) substituents; 1 to 3 independently selected R^(f)substituents; or 1 to 3 independently selected R^(g) substituents. Insome instance, Q¹ is phenyl, 1-naphthyl or 2-naphthyl, F, Cl, Br, I,—CN, —OH, —CF₃, NH₂, CF₃O—, CH₃—, CH₃O, —NO₂, cyclopropyl,cyclopropylmethyl, cyclopropylamino, cyclopropylmethylamino,1-cyanocyclopropyl, methylamino, dimethylamino, methylthio, acetoxy,acetyl, methoxycarbonyl, acetamido, 1-cyclopropylethyl,2-cyclopropylethyl, 1-cyclopropylethylamino, 2-cyclopropylethylamino or1-hydroxy-1-methylethyl or methylcarbamoyl. All the other variables Q²,R¹, R², R³ and R⁴ are as defined in formula (I) and any embodiments asdescribed herein.

In some embodiments of compounds of formula (Ib-1a), Q¹ is1H-4-benzotriazolyl, 1H-5-benzotriazolyl, 1H-4-benzimidazolyl,1H-5-benzimidazolyl, 1H-4-indazolyl, 1H-5-indazolyl, 1H-6-indazolyl,1H-7-indazolyl, 1H-4-indolyl, 1H-5-indolyl, 1H-6-indolyl, 1H-7-indolyl,2-oxo-6-indolinyl, 2-oxo-4-indolinyl, 2-oxo-5-indolinyl,2-oxo-7-indolinyl, 1,2-benzoxazol-4-yl, 1,2-benzoxazol-5-yl,1,2-benzoxazol-6-yl, 1,2-benzoxazol-7-yl, 1,3-benzoxazol-4-yl,1,3-benzoxazol-5-yl, 1,3-benzoxazol-6-yl, 1,3-benzoxazol-7-yl,1,2-benzothiazol-4-yl, 1,2-benzothiazol-5-yl, 1,2-benzothiazol-6-yl,1,2-benzothiazol-7-yl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl,8-quinolinyl, 5-isoquinolinyl, 6-isoquinolinyl, 7-isoquinolinyl,8-isoquinolinyl, 5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl,5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, 8-quinazolinyl,5-quinoxalinyl, 6-quinoxalinyl, 7-quinoxalinyl, 8-quinoxalinyl,4-indanyl, 5-indanyl, 5-tetralinyl, 6-tetralinyl,1,3-dihydroisobenzofuran-4-yl, 1,3-dihydroisobenzofuran-5-yl,2,3-dihydrobenzofuran-4-yl, 2,3-dihydrobenzofuran-5-yl,2,3-dihydrobenzofuran-6-yl, 2,3-dihydrobenzofuran-7-yl,1,3-dihydroisobenzothiophen-4-yl, 1,3-dihydroisobenzothiophen-5-yl,2,3-dihydrobenzothiophen-4-yl, 2,3-dihydrobenzothiophen-5-yl,2,3-dihydrobenzothiophen-6-yl, 2,3-dihydrobenzothiophen-7-yl,4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl, 5-isochromanyl,6-isochromanyl, 7-isochromanyl, 8-isochromanyl, 5-chromanyl,6-chromanyl, 7-chromanyl, 8-chromanyl, 2,3-dihydro-1,3-benzothiazo-4-yl,2,3-dihydro-1,3-benzothiazo-5-yl, 2,3-dihydro-1,3-benzothiazo-6-yl,2,3-dihydro-1,3-benzothiazo-7-yl, 2,3-dihydro-1,2-benzothiazo-4-yl,2,3-dihydro-1,2-benzothiazo-5-yl, 2,3-dihydro-1,2-benzothiazo-6-yl,2,3-dihydro-1,2-benzothiazo-7-yl, 2,3-dihydro-1,3-benzoxazol-4-yl,2,3-dihydro-1,3-benzoxazol-5-yl, 2,3-dihydro-1,3-benzoxazol-6-yl,2,3-dihydro-1,3-benzoxazol-7-yl, 2,3-dihydro-1,2-benzoxazol-4-yl,2,3-dihydro-1,2-benzoxazol-5-yl, 2,3-dihydro-1,2-benzoxazol-6-yl,2,3-dihydro-1,2-benzoxazol-7-yl, 4-benzofuranyl, 5-benzofuranyl,6-benzofuranyl, 7-benzofuranyl, 4-benzothiophenyl, 5-benzothiophenyl,6-benzothiophenyl or 7-benzothiophenyl, each of which is optionallysubstituted with from 1 to 3 independently selected R⁷ substituents; or1 to 3 independently selected R^(a) substituents; or 1 to 3independently selected R^(b) substituents; or 1 to 3 independentlyselected R^(c) substituents; or 1 to 3 independently selected R^(d)substituents; or 1 to 3 independently selected R^(e) substituents; 1 to3 independently selected R^(f) substituents; or 1 to 3 independentlyselected R^(g) substituents. All the other variables Q², R¹, R², R³ andR⁴ are as defined in formula (I) and any embodiments as describedherein.

In some embodiments of compounds of formula (Ib-1a), Q′ is5-pyrimidinyl, 2-pyrimidinyl, 4-pyrimidinyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-pyrazinyl, 2-pyridazinyl, 3-pyridazinyl, 1-pyrrolyl,2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 1-pyrazolyl,2-pyrazolyl, 3-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl,1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-3-yl,1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-1-yl,1,2,4-triazol-2-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl,1,2,4-triazol-5-yl, 1-oxa-2,3-diazol-4-yl, 1-oxa-2,3-diazol-5-yl,1-oxa-2,4-diazol-3-yl, 1-oxa-2,4-diazol-5-yl, 1-oxa-2,5-diazol-3-yl,1-oxa-2,5-diazol-4-yl, 1-thia-2,3-diazol-4-yl, 1-thia-2,3-diazol-5-yl,1-thia-2,4-diazol-3-yl, 1-thia-2,4-diazol-5-yl, 1-thia-2,5-diazol-3-yl,1-thia-2,5-diazol-4-yl, 1-tetrazolyl, 3-tetrazolyl, 1H-5-tetrazolyl,3H-5-tetrazolyl, 2-furanyl, 3-furanyl, 2-thiopenyl or 3-thiophenyl, eachof which is optionally substituted with from 1 to 3 independentlyselected R⁷ substituents; or 1 to 3 independently selected R^(a)substituents; or 1 to 3 independently selected R^(b) substituents; or 1to 3 independently selected R^(c) substituents; or 1 to 3 independentlyselected R^(d) substituents; or 1 to 3 independently selected R^(e)substituents; 1 to 3 independently selected R^(f) substituents; or 1 to3 independently selected R^(g) substituents. All the other variables Q²,R¹, R², R³ and R⁴ are as defined in formula (I) and any embodiments asdescribed herein.

In some embodiments of compounds of formula (Ib-1a), Q¹ is1-benzotriazolyl, 1-benzimidazolyl, 1H-2-benzimidazolyl, 1-indazolyl,1H-3-indazolyl, 1-indolyl, 1H-2-indolyl, 1H-3-indolyl,1,2-benzoxazol-3-yl, 1,3-benzoxazol-2-yl, 1,2-benzothiazol-3-yl,1,3-benzothiazol-2-yl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl,1-isoquinolinyl, 3-isoquinolinyl, 4-isoquinolinyl, 3-cinnolinyl,4-cinnolinyl, 2-quinazolinyl, 4-quinazolinyl, 2-quinoxalinyl,2-benzofuranyl, 3-benzofuranyl, 2-benzothiophenyl or 3-benzothiophenyl,each of which is optionally substituted with from 1 to 3 independentlyselected R⁷ substituents; or 1 to 3 independently selected R^(a)substituents; or 1 to 3 independently selected R^(b) substituents; or 1to 3 independently selected R^(c) substituents; or 1 to 3 independentlyselected R^(d) substituents; or 1 to 3 independently selected R^(e)substituents; 1 to 3 independently selected R^(f) substituents; or 1 to3 independently selected R^(g) substituents. All the other variables Q²,R¹, R², R³ and R⁴ are as defined in formula (I) and any embodiments asdescribed herein.

In a sixth group of embodiments, compounds of formulas (I), (Ib) or(Ib-1) have subformula (Ib-1b):

In some embodiments, R³ is H. In other embodiments, R⁴ is F, Cl, CH₃, CNor CF₃. In other embodiments, R⁴ is F or Cl. In one embodiment, R⁴ is F.In another embodiment, R⁴ is CH₃. In one embodiment, Q² is H. Thevariables Q¹, Q², R³, R⁴, R⁸, R⁹ and R¹⁰ are as defined in anyembodiments of formulas (I) or (Ib) or (Ib-1b) as described herein.

In a seventh group of embodiments, compounds of formula (I) havesubformula (Ic):

Y is —N(R¹)(R²) or —C(R⁸)(R⁹)(R¹⁰). R⁴ is H or F.

is a single bond or a double bond to maintain that the 5-membered ringcontaining Y², Y³ and Y⁴ being aromatic. Y², Y³ and Y⁴ are eachindependently selected from C, O, N, or S, with the proviso at least oneof Y², Y³ and Y⁴ is a heteroatom, where N and S are optionally oxidized.R¹⁶ is H, optionally substituted aryl or optionally substitutedC₁₋₆alkyl; or R⁷; or R^(a); or R^(b); or R^(c); or R^(d); or R^(e); orR^(f); or R^(g). The subscript n is 1, 2 or 3. The variables R¹, R², R³,L and G are as defined in any of the embodiments of formula (I)described herein. In one instance, R³ is H. In one instance, L is abond. In one instance, Y² is N. In another instance, G is6-membered-heteroaryl optionally substituted with a R⁷ substituent; or aR^(a) substituent; or a R^(b) substituent; or a R^(c) substituent; or aR^(d) substituent; or a R^(e) substituent; or a R^(f) substituent; or aR^(g) substituent. In another instance, G is 4-pyrimidinyl optionallysubstituted with a R⁷ substituent; or a R^(a) substituent; or a R^(b)substituent; or a R^(c) substituent; or a R^(d) substituent; or a R^(e)substituent; or a R^(f) substituent; or a R^(g) substituent. In anotherinstance, G is 2-amino-4-pyrimidinyl optionally substituted with a R⁷substituent; or a R^(a) substituent; or a R^(b) substituent; or a R^(c)substituent; or a R^(d) substituent; or a R^(e) substituent; or a R^(f)substituent; or a R^(g) substituent. The variables Y, R³, R⁴, L, Y², Y³and Y⁴ are as defined in any of embodiments of formula (I) as describedherein.

In an eighth group of embodiments, compounds of formula (I) or (Ic) havesubformula (Ic-1):

In one embodiment, R³ is H. In some instances, both R³ and R⁴ are H. Inone embodiment, Y² is N. In one embodiment, the subscript n is 1. Inanother embodiment, the subscript is 2. In another embodiment, thesubscript is 3. In some embodiments, Y² is N, Y³ is C and Y⁴ is S. Inother embodiments, Y² is N, Y³ is C and Y⁴ is O. In other embodiments,Y² is S, Y³ is C and Y⁴ is N. In other embodiments, Y² is O, Y³ is C andY⁴ is N. In other embodiments, Y² is N, Y³ is C and Y⁴ is N. In certainembodiments, —N(R¹)(R²) is 1-azetidinyl, 1-pyrrolidinyl or1-piperidinyl, each of which is optionally substituted. In certaininstances, —N(R¹)(R²) is 1-azetidinyl, 1-pyrrolidinyl or 1-piperidinyl,each of which is optionally substituted with from 1-2 independentlyselected R⁷ substituents; or 1 to 2 independently selected R^(a)substituents; or 1 to 2 independently selected R^(b) substituents; or 1to 2 independently selected R^(c) substituents; or 1 to 2 independentlyselected R^(d) substituents; or 1 to 2 independently selected R^(e)substituents; or 1 to 2 independently selected R^(f) substituents; or 1to 2 independently selected R^(g) substituents; or 1-2 halogen. In otherinstances, R¹ is CH₃ and R² is C₁₋₆alkyl. In other instances, R¹ is CH₃and R² is ethyl. In other instances, R¹ and R² are CH₃. In otherinstances, R¹ and R² are ethyl. The variables R¹, R², R³, R⁴, R¹⁶, L, n,G, Y², Y³ and Y⁴ are as defined in any of embodiments of formula (I) or(Ic) as described herein.

In a ninth group of embodiments, compounds of formulas (I), (Ic) or(Ic-1) have subformula (Ic-1a):

R¹⁹ is H; or R⁷; or R^(a); or R^(b); or R^(c); or R^(d); or R^(e);R^(f); or R^(g) substituent. In one embodiment, R¹⁹ is H. In anotherembodiment, R¹⁹ is 2-(methoxycarbonylamino)propyl. In yet anotherembodiment, R¹⁹ is (R)-2-(methoxycarbonylamino)propyl. In still anotherembodiment, R¹⁹ is (S)-2-(methoxycarbonylamino)propyl. The variables R¹,R², R⁴ and R¹⁶ are as defined in any of the embodiments of formula (I)or its subformulas as described herein. In one embodiment, R¹⁶ is H,phenyl or C₁₋₆alkyl, wherein the phenyl or alkyl is optionallysubstituted with from 1 to 3 independently selected R⁷ substituents; or1 to 3 independently selected R^(a) substituents; or 1 to 3independently selected R^(b) substituents; or 1 to 3 independentlyselected R^(c) substituents; or 1 to 3 independently selected R^(d)substituents; or 1 to 3 independently selected R^(e) substituents; 1 to3 independently selected R^(f) substituents; or 1 to 3 independentlyselected R^(g) substituents. In one embodiment, R⁴ is H. In anotherembodiment, R⁴ is F or Cl. In yet another embodiment, R⁴ is F, Cl, CH₃,CN or CF₃. In certain embodiments, R¹ and R² taken together with thenitrogen atom to which they attach form 1-azetidinyl, 1-pyrrolidinyl or1-piperidinyl, each of which is optionally substituted with from 1-2independently selected R⁷ substituents; or 1 to 2 independently selectedR^(a) substituents; or 1 to 2 independently selected R^(b) substituents;or 1 to 2 independently selected R^(c) substituents; or 1 to 2independently selected R^(d) substituents; or 1 to 2 independentlyselected R^(e) substituents; or 1 to 2 independently selected R^(f)substituents; or 1 to 2 independently selected R^(g) substituents; or1-2 halogen. In other instances, R¹ is CH₃ and R² is C₁₋₆alkyl. In otherinstances, R¹ is CH₃ and R² is ethyl. In other instances, R¹ and R² areCH₃. In other instances, R¹ and R² are ethyl.

In a tenth group of embodiments, compounds of formula (I) or (Ic) havesubformula (Ic-2):

In one embodiment, R³ is H. In certain embodiments, —C(R⁸)(R⁹)(R¹⁰) iscyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which isoptionally substituted. In certain instances, —C(R⁸)(R⁹)(R¹⁰) iscyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which isoptionally substituted with from 1-2 independently selected R⁷substituents; or 1 to 2 independently selected R^(a) substituents; or 1to 2 independently selected R^(b) substituents; or 1 to 2 independentlyselected R^(c) substituents; or 1 to 2 independently selected R^(d)substituents; or 1 to 2 independently selected R^(e) substituents; or 1to 2 independently selected R^(f) substituents; or 1 to 2 independentlyselected R^(g) substituents. The variables R⁸, R⁹, R¹⁰, R³, R⁴, R¹⁶, L,n, G, Y², Y³ and Y⁴ are as defined in any of embodiments of formula (I)or any of the subgeneric formulas of formula (I) as described herein.

In an eleventh group of embodiments, compounds of formulas (I), (Ic) or(Ic-2) have subformula (Ic-2a):

R¹⁹ is H; or R⁷; or R^(a); or R^(b); or R^(c); or R^(d); or R^(e);R^(f); or R^(g) substituent. In one embodiment, R¹⁹ is H. In anotherembodiment, R¹⁹ is 2-(methoxycarbonylamino)propyl. R¹⁶ is H, phenyl orC₁₋₆alkyl, wherein the phenyl or alkyl is optionally substituted withfrom 1 to 3 independently selected R⁷ substituents; or 1 to 3independently selected R^(a) substituents; or 1 to 3 independentlyselected R^(b) substituents; or 1 to 3 independently selected R^(c)substituents; or 1 to 3 independently selected R^(d) substituents; or 1to 3 independently selected R^(e) substituents; 1 to 3 independentlyselected R^(f) substituents; or 1 to 3 independently selected R^(g)substituents. The variables R⁸, R⁹, R¹⁰, R¹⁶, and R⁴ are as defined inany of the embodiments of formula (I) or its subformulas as describedherein. In one embodiment, R⁴ is H. In another embodiment, R⁴ is F orCl. In yet another embodiment, R⁴ is F, Cl, CH₃, CN or CF₃. In certainembodiments, R¹⁰ is H and R⁸ and R⁹ taken together with the carbon atomto which they attach form cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl, each of which is optionally substituted with from 1-2independently selected R⁷ substituents; or 1 to 2 independently selectedR^(a) substituents; or 1 to 2 independently selected R^(b) substituents;or 1 to 2 independently selected R^(c) substituents; or 1 to 2independently selected R^(d) substituents; or 1 to 2 independentlyselected R^(e) substituents; or 1 to 2 independently selected R^(f)substituents; or 1 to 2 independently selected R^(g) substituents.

In a twelfth group of embodiments, compounds of formula (I) havesubformula (Id):

R⁴ is H, Cl or F. The subscript n is 1 or 2. The variables Y, R³, R⁴,Y², Y³, Y⁴, R¹⁶, L, n and G are as defined in any of the embodiments offormulas (I), (Ic) or (Ic-1) as described herein. In one embodiment, Lis a bond. In some instances, Y² is N, Y³ is N and Y⁴ is C. In otherinstances, Y² is C, Y³ is N and Y⁴ is N. In other instances, Y² is N, Y³is O and Y⁴ is C. In other instances, Y² is C, Y³ is O and Y⁴ is N. Inother instances, Y² is N, Y³ is S and Y⁴ is C. In other instances, Y² isC, Y³ is S and Y⁴ is N. In other instances, Y² is N, Y³ is N and Y⁴ isN.

In a thirteenth group of embodiments, compounds of formulas (I) or (Id)have subformula (Id-1):

The subscript n is 1, 2 or 3. The variables R¹, R², R³, R⁴, Y², Y³, Y⁴,R¹⁶, n and G are as defined in any of the embodiments of formulas (I),(Ic), (Ic-1) or (Id) as described herein.

In a fourteenth group of embodiments, compounds of formulas (I), (Id) or(Id-1) have sub formula (Id-1a):

The variables R¹, R², R⁴, R¹⁶ and R¹⁹ are as defined in any of theembodiments of formulas (I) or its subgeneric formulas as describedherein. In one embodiment, R⁴ is H or F. In another embodiment, R⁴ is H,F, Cl, CH₃, CN or CF₃. In another embodiment, R¹⁶ is H, phenyl orC₁₋₆alkyl, wherein the phenyl or alkyl is optionally substituted withfrom 1 to 3 independently selected R⁷ substituents; or 1 to 3independently selected R^(a) substituents; or 1 to 3 independentlyselected R^(b) substituents; or 1 to 3 independently selected R^(c)substituents; or 1 to 3 independently selected R^(d) substituents; or 1to 3 independently selected R^(e) substituents; 1 to 3 independentlyselected R^(f) substituents; or 1 to 3 independently selected R^(g)substituents. In one embodiment, R¹⁹ is H; or R⁷; or R^(a); or R^(b); orR^(c); or R^(d); or R^(e); R^(f); or R^(g) substituent; or2-(methoxycarbonylamino)propyl. In another embodiment, R¹⁹ is(R)-2-(methoxycarbonylamino)propyl. In yet another embodiment, R¹⁹ is(S)-2-(methoxycarbonylamino)propyl. In some embodiments, R¹ and R² takentogether with the nitrogen atom to which they attach form 1-azetidinyl,1-pyrrolidinyl or 1-piperidinyl, each of which is optionally substitutedwith from 1-2 independently selected R⁷ substituents; or 1 to 2independently selected R^(a) substituents; or 1 to 2 independentlyselected R^(b) substituents; or 1 to 2 independently selected R^(c)substituents; or 1 to 2 independently selected R^(d) substituents; or 1to 2 independently selected R^(e) substituents; or 1 to 2 independentlyselected R^(f) substituents; or 1 to 2 independently selected R^(g)substituents; or 1-2 halogen. In other instances, R¹ is CH₃ and R² isC₁₋₆alkyl. In other instances, R¹ is CH₃ and R² is ethyl. In otherinstances, R¹ and R² are CH₃. In other instances, R¹ and R² are ethyl.

In a fifteenth group of embodiments, compounds of formulas (I) or (Id)have subformula (Id-2):

The variables R⁸, R⁹, R¹⁰, R³, R⁴, L, Y², Y³, Y⁴, R¹⁶, n and G are asdefined in any of the embodiments of formulas (I) or its subgenericformulas, for example, formulas (Ic), (Ic-1), (Id) or (Id-1) asdescribed herein.

In a sixteenth group of embodiments, compounds of formulas (I), (Id) or(Id-2) have subformula (Id-2a):

The variables R⁸, R⁹, R¹⁰, R⁴, R¹⁶ and R¹⁹ are as defined in any of theembodiments of formulas (I) or its subgeneric formulas, for example,formulas (Ic), (Ic-1), (Id), (Id-1) or (Id-2) as described herein.

In a seventeenth group of embodiments, compounds of formula (I) havesubformula (Ie):

The variables Y, R³, R⁴, L, Y², Y³, Y⁴, R¹⁶, n and G are as defined inany of embodiments of formula (I) or any of the subgeneric formulas offormula (I) as described herein. In some embodiments, Y is —N(R¹)(R²) or—C(R⁸)(R⁹)(R¹⁰), where R¹, R², R⁸, R⁹ and R¹⁰ are as defined any of theembodiments of formula (I) described herein. In other embodiments, R⁴ isF, Cl, CN, CH₃ or CF₃. In one instance, R⁴ is F or Cl. In oneembodiment, L is a bond.

is a single bond or a double bond. Y², Y³ and Y⁴ are each independentlyselected from C, O, N, or S, with the proviso at least one of Y², Y³ andY⁴ is a heteroatom, where N and S are optionally oxidized. R¹⁶ is H,optionally substituted aryl or optionally substituted C₁₋₆alkyl; or R⁷;or R^(a); or R^(b); or R^(c); or R^(d); or R^(e); or R^(f); or R^(g).The subscript n is 1, 2 or 3. The variables R¹, R², R³, L and G are asdefined in any of the embodiments of formula (I) described herein. Inone instance, R³ is H. In one instance, L is a bond. In one instance, Y²is N. In another instance, G is 6-membered-heteroaryl optionallysubstituted with a R⁷ substituent; or a R^(a) substituent; or a R^(b)substituent; or a R^(c) substituent; or a R^(d) substituent; or a R^(e)substituent; or a R^(f) substituent; or a R^(g) substituent. In anotherinstance, G is 4-pyrimidinyl optionally substituted with a R⁷substituent; or a R^(a) substituent; or a R^(b) substituent; or a R^(c)substituent; or a R^(d) substituent; or a R^(e) substituent; or a R^(f)substituent; or a R^(g) substituent. In another instance, G is2-amino-4-pyrimidinyl optionally substituted with a R⁷ substituent; or aR^(a) substituent; or a R^(b) substituent; or a R^(c) substituent; or aR^(d) substituent; or a R^(e) substituent; or a R^(f) substituent; or aR^(g) substituent.

In an eighteenth group of embodiments, compounds of formula (I) or (Ie)have subformula (Ie-1):

The subscript n is 1, 2 or 3. The variables R¹, R², R³, R⁴, Y², Y³, Y⁴,L, R¹⁶, n and G are as defined in any of the embodiments of formulas(I), (Ic), (Ic-1), (Id), (Id-1), (Id-1a) or (Ie) as described herein.

In a nineteenth group of embodiments, compounds of formula (I), (Ie) or(Ie-1) have subformula (Ie-1a):

The variables R¹, R², R³, R⁴, R¹⁶, R¹⁹, n, Y², Y³ and Y⁴ are as definedin any of the embodiments of formulas (I) or its subgeneric formulas asdescribed herein. In one embodiment, R³ is H. In another embodiment, R⁴is F or Cl. In some embodiments, R¹⁹ is H; or R⁷; or R^(a); or R^(b); orR^(c); or R^(d); or R^(e); R^(f); or R^(g) substituent; or2-(methoxycarbonylamino)propyl. In another embodiment, R¹⁹ is(R)-2-(methoxycarbonylamino)propyl. In yet another embodiment, R¹⁹ is(S)-2-(methoxycarbonylamino)propyl. In one embodiment, Y² is N, Y³ andY⁴ are C. In another embodiment, Y² is O, Y³ and Y⁴ are C. In anotherembodiment, Y⁴ is N, Y³ and Y² are C. In another embodiment, Y⁴ is O, Y³and Y² are C. In another embodiment, Y⁴ is O, Y³ is C and Y² is N. Inanother embodiment, Y³ is N, Y² is N and Y⁴ are C. In anotherembodiment, Y³ is N, Y² is O and Y⁴ are C. In another embodiment, Y³ isN, Y² is N and Y⁴ is N. In another embodiment, Y³ is N, Y² is O and Y⁴is N. In another embodiment, Y³ is C, Y² is C and Y⁴ is N. In anotherembodiment, Y³ is C, Y² is N and Y⁴ is N. In another embodiment, Y³ isN, Y² is C and Y⁴ is N. In another embodiment, Y⁴ is S, Y³ is C and Y²is N.

In a twentieth group of embodiments, compounds of formula (I) or (Ie)have subformula (Ie-2):

The variables R⁸, R⁹, R¹⁰, R³, R⁴, L, Y², Y³, Y⁴, R¹⁶, n and G are asdefined in any of the embodiments of formulas (I) or its subgenericformulas, for example, formulas (Ic), (Ic-1), (Id), (Id-1), (Ie) or(Ie-1) as described herein.

In a twenty-first group of embodiments, compounds of formula (I), (Ie)or (Ie-2) have subformula (Ie-2a):

The variables R⁸, R⁹, R¹⁰, R³, R⁴, L, Y², Y³, Y⁴, R¹⁶, n and G are asdefined in any of the embodiments of formulas (I) or its subgenericformulas as described herein. In one embodiment, R⁴ is Cl or F. Inanother embodiment, R³ is H. In some embodiments, R¹⁹ is H; or R⁷; orR^(a); or R^(b); or R^(c); or R^(d); or R^(e); R^(f); or R^(g)substituent; or 2-(methoxycarbonylamino)propyl. In another embodiment,R¹⁹ is (R)-2-(methoxycarbonylamino)propyl. In yet another embodiment,R¹⁹ is (S)-2-(methoxycarbonylamino)propyl. In one embodiment, Y² is N,Y³ and Y⁴ are C. In another embodiment, Y² is O, Y³ and Y⁴ are C. Inanother embodiment, Y⁴ is N, Y³ and Y² are C. In another embodiment, Y⁴is O, Y³ and Y² are C. In another embodiment, Y⁴ is O, Y³ is C and Y² isN. In another embodiment, Y³ is N, Y² is N and Y⁴ are C. In anotherembodiment, Y³ is N, Y² is O and Y⁴ are C. In another embodiment, Y³ isN, Y² is N and Y⁴ is N. In another embodiment, Y³ is N, Y² is O and Y⁴is N. In another embodiment, Y³ is C, Y² is C and Y⁴ is N. In anotherembodiment, Y³ is C, Y² is N and Y⁴ is N. In another embodiment, Y³ isN, Y² is C and Y⁴ is N. In another embodiment, Y⁴ is S, Y³ is C and Y²is N. In certain embodiments, R¹⁰ is H and R⁸ and R⁹ taken together withthe carbon atom to which they attach form cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl, each of which is optionally substituted withfrom 1-2 independently selected R⁷ substituents; or 1 to 2 independentlyselected R^(a) substituents; or 1 to 2 independently selected R^(b)substituents; or 1 to 2 independently selected R^(c) substituents; or 1to 2 independently selected R^(d) substituents; or 1 to 2 independentlyselected R^(e) substituents; or 1 to 2 independently selected R^(f)substituents; or 1 to 2 independently selected R^(g) substituents.

In a twenty-second group of embodiments, compounds of formula (I) havesubformula (If):

The variables Q², R³, R⁴ and Y are as defined in any of the embodimentsof compounds of formula (I) and its subgeneric formulas as describedherein. In some instances, R³ is H. In other instances, R⁴ is H, F orCl.

In a twenty-third group of embodiments, compounds of formula (I) or (If)have subformula (If-1) or (If-2):

R⁴ is H, F or Cl. The variables Q², R³, R¹, R², R⁸, R⁹ and R¹⁰ are asdefined in any of the embodiments of compounds of formula (I) and itssubgeneric formulas as described herein.

In a twenty-fourth group of embodiments, compounds of formula (I) or(If) have subformula (If-3) or (If-4):

The variables Q², R³, R⁴, R¹, R², R⁸, R⁹ and R¹⁰ are as defined in anyof the embodiments of compounds of formula (I) and its subgenericformulas as described herein. In some embodiments, R⁴ is F or Cl. Inother embodiments, R³ is H.

In a twenty-fifth group of embodiments, compounds of formula (I) havesubformula (Ig):

The variables Q², R³, R⁴ and Y are as defined in any of the embodimentsof compounds of formula (I) and its subgeneric formulas as describedherein. In some instances, R³ is H. In other instances, R⁴ is H, F orCl. In some instances, when Q² is optionally substitutedcycloalkylalkyl, Y is not —N(R¹)(R²), wherein R¹ and R² are eachindependently alkyl. In other instances, when Q² is cycloalkylalkyl, Yis not —N(CH₃)(CH₂CH₃). In some instances, when Q² is 1-cyclopropylethyland Y is not —N(CH₃)(CH₂CH₃). In some embodiments, Q² is C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, aryl, arylalkyl,heteroaryl or heteroarylalkyl, each of which is optionally substitutedand Y is an optionally substituted heterocycloalkyl as defined herein.In certain instances, Y is —N(R¹)(R²) or —C(R⁸)(R⁹)(R¹⁰, where R¹ and R²taken together with the nitrogen atom to which they are attached form anoptionally substituted 5-membered heterocycloalkyl ring.

In a twenty-sixth group of embodiments, compounds of formula (I) or (Ig)have subformulas (Ig-1) or (Ig-2):

R⁴ is H, F or Cl. The variables Q², R³, R¹, R², R⁸, R⁹ and R¹⁰ are asdefined in any of the embodiments of compounds of formula (I) and itssubgeneric formulas as described herein.

In a twenty-seventh group of embodiments, compounds of formula (I) or(Ig) have subformulas (Ig-3) or (Ig-4):

The variables Q², R³, R⁴, R¹, R², R⁸, R⁹ and R¹⁰ are as defined in anyof the embodiments of compounds of formula (I) and its subgenericformulas as described herein. In some embodiments, R⁴ is F or Cl. Inother embodiments, R³ is H. In some embodiments, Q² is C₁₋₆alkyl, C₃₋₆cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄alkyl, heterocycloalkyl orheterocycloalkylC₁₋₄alkyl, each of which is optionally substituted withfrom 1-3 independently selected R⁷; or 1 to 3 independently selectedR^(a) substituents; or 1 to 3 independently selected R^(b) substituents;or 1 to 3 independently selected R^(c) substituents; or 1 to 3independently selected R^(d) substituents; or 1 to 3 independentlyselected R^(e) substituents; or 1 to 3 independently selected R^(f)substituents; or 1 to 3 independently selected R^(g) substituents.

In a twenty-eighth group of embodiments, compounds of formula (I) havesubformula (Ih):

The variables Y, R³, R⁴ and R¹⁹ are as defined in any of the embodimentsof compounds of formula (I) and its subgeneric formulas as describedherein. In one embodiment, le is C₁₋₆alkyl-C(O)—. In another embodiment,R¹⁹ is CH₃C(O)—.

In a twenty-ninth group of embodiments, compounds of formula (I) havesubformulas (Ih-1) or (Ih-2):

R⁴ is H, F or Cl. The variables R³, R¹, R², R⁸, R⁹, R¹⁰ and R¹⁹ are asdefined in any of the embodiments of compounds of formula (I) or any ofsubgeneric formulas of formula (I) as described herein.

In a thirtieth group of embodiments, compounds of formula (I) havesubformulas (Ih-3) or (Ih-4):

R⁴ is F, Cl, CH₃, CN, CF₃, CHF₂, CH₂F or CH₃O. In some embodiments, R⁴is F or Cl. In other embodiments, R⁴ is F, Cl or CH₃ The variables R³,R¹, R², R⁸, R⁹, R¹⁰ and R¹⁹ are as defined in any of the embodiments ofcompounds of formula (I) or any of subgeneric formulas of formula (I) asdescribed herein.

In a thirty-first group of embodiments, compounds of formula (I) havesubformulas (Ij), (Ij-1) or (Ij-2):

The variables R³, R⁴, R¹, R², R⁸, R⁹, R¹⁰, Q¹, Q² and Y are as definedin any of the embodiments of compounds of formula (I) or any ofsubgeneric formulas of formula (I) as described herein. In oneembodiment, Q¹ is H or halogen. In another embodiment, Q¹ is H. In oneembodiment, Q² is halogen, CN, CH₃O— or cyclopropylmethylamino. In oneembodiment, R⁴ is H or F. In one embodiment, R³ is H.

Some embodiments disclosed herein can include compound as set forth inTable 1 or a pharmaceutically acceptable salt, hydrates, solvates,isomers, tautomers or deuterated analogs thereof.

TABLE 1 Com- (MS pound (ESI) No. Name Structure [M + H⁺]⁺) P-2001N-[2,4-difluoro-3-(4-methoxy-1H- pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl]propane-2-sulfonamide

409.9 P-2002 3-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-4-methoxy-1H- pyrrolo[2,3-b]pyridine

411.1 P-2003 N-[2,4-difluoro-3-(4-methoxy-1H- pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl]pyrrolidine-1-sulfonamide

437.1 P-2004 3-[3-(diethylsulfamoylamino)-2,6-difluoro-benzoyl]-4-methoxy-1H-pyrrolo[2,3- b]pyridine

439.1 P-2005 N-[2,4-difluoro-3-(4-methoxy-1H- pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl]cyclohexanesulfonamide

449.9 P-2006 N-[2,4-difluoro-3-(4-methoxy-1H- pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl]butane-2-sulfonamide

423.9 P-2007 4-chloro-3-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3- b]pyridine

415.1 P-2008 N-[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro- phenyl]cyclobutanesulfonamide

425.9 P-2009 N-[2,4-difluoro-3-(4-methoxy-1H- pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl]pentane-2-sulfonamide

437.9 P-2010 N-[2,4-difluoro-3-(4-methoxy-1H- pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl]cyclobutanesulfonamide

421.9 P-2011 4-chloro-3-[3-(diethylsulfamoylamino)-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3- b]pyridine

443.1 P-2012 4-cyano-3-[3-(diethylsulfamoylamino)-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3- b]pyridine

433.9 P-2013 N-[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]propane-2- sulfonamide

413.9 P-2014 N-[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro- phenyl]cyclohexanesulfonamide

453.9 P-2015 N-[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro- phenyl]cyclopentanesulfonamide

439.9 P-2016 N-[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]butane-2- sulfonamide

427.9 P-2017 N-[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]propane-2 sulfonamide

405.1 P-2018 N-[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro- phenyl]cyclohexanesulfonamide

445.1 P-2019 N-[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro- phenyl]pyrrolidine-1-sulfonamide

431.9 P-2020 N-[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]butane-2- sulfonamide

419.1 P-2021 N-[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro- phenyl]cyclobutanesulfonamide

417.5 P-2022 N-[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro- phenyl]morpholine-4-sulfonamide

447.9 P-2023 N-[2,4-difluoro-3-(4-methoxy-1H- pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl]morpholine-4-sulfonamide

453.1 P-2024 N-[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro- phenyl]morpholine-4-sulfonamide

457.1 P-2025 N-[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro- phenyl]pyrrolidine-1-sulfonamide

441.1 P-2026 5-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-7H-pyrrolo[2,3- d]pyrimidine

381.9 P-2027 N-[2,4-difluoro-3-(7H-pyrrolo[2,3- d]pyrimidine-5-carbonyl)phenyl]cyclohexanesulfonamide

421.1 P-2028 N-[2,4-difluoro-3-(7H-pyrrolo[2,3- d]pyrimidine-5-carbonyl)phenyl]cyclopentanesulfonamide

407.1 P-2029 N-[2,4-difluoro-3-(7H-pyrrolo[2,3- d]pyrimidine-5-carbonyl)phenyl]pyrrolidine-1-sulfonamide

408.3 P-2030 N-[2,4-difluoro-3-(7H-pyrrolo[2,3- d]pyrimidine-5-carbonyl)phenyl]cyclobutanesulfonamide

393.1 P-2031 N-[2,4-difluoro-3-(7H-pyrrolo[2,3- d]pyrimidine-5-carbonyl)phenyl]morpholine-4-sulfonamide

424.3 P-2032 N-[2-fluoro-3-(7H-pyrrolo[2,3- d]pyrimidine-5-carbonyl)phenyl]pyrrolidine-1-sulfonamide

390.3 P-2033 N-(6-acetamido-3-pyridyl)-2,6-difluoro-3-(1-piperidylsulfonylamino)benzamide

454.3 P-2034 N-(6-acetamido-3-pyridyl)-3-(dimethylsulfamoylamino)-2,6-difluoro- benzamide

414.3 P-2035 N-(6-acetamido-3-pyridyl)-3-(cyclopentylsulfonylamino)-2,6-difluoro- benzamide

439.1 P-2036 N-(6-acetamido-3-pyridyl)-2,6-difluoro-3-(pyrrolidin-1-ylsulfonylamino)benzamide

P-2037 N-[2,4-difluoro-3-[4-(isopropylamino)-7H-pyrrolo[2,3-d]pyrimidine-5- carbonyl]phenyl]propane-2-sulfonamide

438.0 P-2038 N-[2,4-difluoro-3-[4-(isopropylamino)-7H-pyrrolo[2,3-d]pyrimidine-5- carbonyl]phenyl]piperidine-1-sulfonamide

479.0 P-2039 N-[2,4-difluoro-3-[4-(isopropylamino)-7H-pyrrolo[2,3-d]pyrimidine-5- carbonyl]phenyl]cyclohexanesulfonamide

478.0 P-2040 N-[2,4-difluoro-3-[4-(isopropylamino)-7H-pyrrolo[2,3-d]pyrimidine-5- carbonyl]phenyl]cyclopentanesulfonamide

464.0 P-2041 N-[2,4-difluoro-3-[4-(isopropylamino)-7H-pyrrolo[2,3-d]pyrimidine-5- carbonyl]phenyl]pyrrolidine-1-sulfonamide

465.0 P-2042 5-[3-(diethylsulfamoylamino)-2,6-difluoro-benzoyl]-4-(isopropylamino)-7H- pyrrolo[2,3-d]pyrimidine

467.5 P-2043 N-[2,4-difluoro-3-[4-(isopropylamino)-7H-pyrrolo[2,3-d]pyrimidine-5- carbonyl]phenyl]cyclobutanesulfonamide

450.0 P-2044 N-[2,4-difluoro-3-[4-(isopropylamino)-7H-pyrrolo[2,3-d]pyrimidine-5- carbonyl]phenyl]morpholine-4-sulfonamide

481.0 P-2045 5-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-4-(isopropylamino)-7H- pyrrolo[2,3-d]pyrimidine

439.0 P-2046 N-[3-[4-(cyclopropylmethylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]-2,4-difluoro-phenyl]cyclopropanesulfonamide

448.0 P-2047 N-[3-[4-(cyclopropylmethylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]-2,4-difluoro-phenyl]propane-2-sulfonamide

450.0 P-2048 4-(cyclopropylmethylamino)-5-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-7H-pyrrolo[2,3-d]pyrimidine

P-2049 N-[3-[4-(cyclopropylmethylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]-2,4-difluoro-phenyl]cyclohexanesulfonamide

490.5 P-2050 N-[3-[4-(cyclopropylmethylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]-2,4-difluoro-phenyl]cyclopentanesulfonamide

476.5 P-2051 N-[3-[4-(cyclopropylmethylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]-2,4-difluoro-phenyl]pentane-2-sulfonamide

478.0 P-2052 4-(cyclopropylmethylamino)-5-[3-(diethylsulfamoylamino)-2,6-difluoro-benzoyl]-7H-pyrrolo[2,3-d]pyrimidine

479.0 P-2053 N-[3-[4-(cyclopropylmethylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]-2,4-difluoro-phenyl]cyclobutanesulfonamide

462.5 P-2054 N-[3-[4-(cyclopropylmethylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]-2,4-difluoro-phenyl]morpholine-4-sulfonamide

493.1 P-2055 N-[3-[4-(cyclopropylmethylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide

477.1 P-2056 N-[3-[4-(cyclopropylmethylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]-2,4-difluoro-phenyl]butane-2-sulfonamide

464.3 P-2057 N-[3-[4-(cyclopropylmethylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide

459.4 P-2058 N-[3-[4-(cyclopropylmethylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]-2,4-difluoro-phenyl]tetrahydropyran-4- sulfonamide

492.5 P-2060 N-[3-[4-(cyclopropylmethylamino)-5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]pyrrolidine- 1-sulfonamide

465.1 P-2061 4-(cyclopropylmethylamino)-5-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6- difluoro-benzoyl]-7H-pyrrolo[2,3-d]pyrimidine

407.1 P-2062 5-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-4-(methylamino)-7H- pyrrolo[2,3-d]pyrimidine

433.2 P-2063 4-(cyclopropylamino)-5-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-7H-pyrrolo[2,3-d]pyrimidine

447.0 P-2064 4-(cyclopropylmethylamino)-5-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-7H-pyrrolo[2,3-d]pyrimidine

475.0 P-2065 5-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-4-(2,2,2- trifluoroethylamino)-7H-pyrrolo[2,3-d]pyrimidine

435.2 P-2066 5-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-4-(propylamino)-7H- pyrrolo[2,3-d]pyrimidine

435.4 P-2067 5-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-4-(isopropylamino)-7H- pyrrolo[2,3-d]pyrimidine

511.1 P-2068 4-[(4,4-difluorocyclohexyl)amino]-5-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-7H-pyrrolo[2,3-d]pyrimidine

465.1 P-2069 5-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-4-[(2-hydroxy-2-methyl- propyl)amino]-7H-pyrrolo[2,3-d]pyrimidine

445.4 P-2070 N-[3-[4-(cyclopropylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide

419.3 P-2071 N-[2-fluoro-3-[4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidine-5- carbonyl]phenyl]pyrrolidine-1-sulfonamide

447.3 P-2072 4-(cyclobutylamino)-5-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-7H-pyrrolo[2,3-d]pyrimidine

451.3 P-2073 5-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-4-(2-methoxyethylamino)- 7H-pyrrolo[2,3-d]pyrimidine

477.1 P-2074 5-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-4-[[(2S)-tetrahydrofuran-2-yl]methylamino]-7H-pyrrolo[2,3- d]pyrimidine

477.0 P-2075 5-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-4-(tetrahydropyran-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidine

465.1 P-2076 N-[2-fluoro-3-(4-methyl-7H-pyrrolo[2,3- d]pyrimidine-5-carbonyl)phenyl]pyrrolidinc-1-sulfonamide

402.0* P-2077 N-[2-fluoro-3-[4-(2,2,2-trifluoroethylamino)-7H-pyrrolo[2,3- d]pyrimidine-5-carbonyl]phenyl]pyrrolidine-1-sulfonamide

487.2 P-2078 N-[3-(4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-2-fluoro- phenyl]pyrrolidine-1-sulfonamide

428.1* P-2079 4-[[(1R)-1-cyclopropylethyl]amino]-5-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-7H-pyrrolo[2,3-d]pyrimidine

461.1 P-2080 4-[[(1S)-1-cyclopropylethyl]amino]-5-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fiuoro-benzoyl]-7H-pyrrolo[2,3-d]pyrimidine

461.5 P-2081 N-[3-[4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]-2-fluoro- phenyl]pyrrolidine-1-sulfonamide

459.4 P-2082 N-[2-fluoro-3-[4-[[(2S)-tetrahydrofuran-2-yl]methylamino]-7H-pyrrolo[2,3- d]pyrimidine-5-carbonyl]phenyl]pyrrolidine-1-sulfonamide

489.4 P-2083 N-[2-fluoro-3-[4-(tetrahydropyran-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]phenyl]pyrrolidine-1-sulfonamide

489.1 P-2084 N-[2-fluoro-3-(4-methoxy-7H-pyrrolo[2,3- d]pyrimidine-5-carbonyl)phenyl]pyrrolidine-1-sulfonamide

419.9 P-2085 2-tert-butyl-5-(2-chloropyrimidin-4-yl)-4-[3-[[ethyl(methyl)sulfamoyl]amino]-2- fluoro-phenyl]thiazole

P-2086 5-[2-fluoro-3- [[methyl(propyl)sulfamoyl]amino]benzoyl]-4-methyl-7H-pyrrolo[2,3-d]pyrimidine

P-2087 4-cyclopropyl-5-[2-fluoro-3-[[methyl(propyl)sulfamoyl]amino]benzoyl]- 7H-pyrrolo[2,3-d]pyrimidine

P-2088 2-tert-butyl-4-[3- [[ethyl(methyl)sulfamoyl]amino]-2-fluoro-phenyl]-5-(2-methoxypyrimidin-4- yl)thiazole

P-2089 5-(2-aminopyrimidin-4-yl)-2-tert-butyl-4-[3-[[ethyl(methyl)sulfamoyl]amino]-2- fluoro-phenyl]thiazole

P-2090 5-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-4-methyl-7H-pyrrolo[2,3- d]pyrimidine

P-2091 4-cyclopropyl-5-[3- [[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-7H-pyrrolo[2,3-d]pyrimidine

P-2092 5-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-4-methoxy-7H-pyrrolo[2,3- d]pyrimidine

406.1* P-2093 5-(2-aminopyrimidin-4-yl)-2-tert-butyl-4-[3-(dimethylsulfamoylamino)-2-fluoro- phenyl]thiazole

P-2094 N-[3-[4-[[(1R)-1-cyclopropylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide

473.4 P-2095 N-[3-[4-[(2,2-dimethyl-1,3-dioxolan-4-yl)methylamino]-7H-pyrrolo[2,3- d]pyrimidine-5-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide

519.1 P-2096 N-[3-[4-(2,3-dihydroxypropylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide

479.1 P-2097 1-[[5-[2-fluoro-3-(pyrrolidin-1-ylsulfonylamino)benzoyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]amino]cyclopropanecarboxylic acid

489.0 P-2098 N-[2-fluoro-3-[4-[(3- hydroxycyclobutyl)methylamino]-7H-pyrrolo[2,3-d]pyrimidine-5- carbonyl]phenyl]pyrrolidine-1-sulfonamide

489.1 P-2099 5-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-4-(propylamino)-7H- pyrrolo[2,3-d]pyrimidine

453.2 P-2100 5-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-4-(2- methoxyethylamino)-7H-pyrrolo[2,3- d]pyrimidine

469.1 P-2101 4-(cyclobutylamino)-5-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6- difluoro-benzoyl]-7H-pyrrolo[2,3-d]pyrimidine

465.0 P-2102 N-[3-[4-(2-aminoethylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide

448.0 P-2103 ethyl 2-[[5-[2-fluoro-3-(pyrrolidin-1-ylsulfonylamino)benzoyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]amino]acetate

491.2 P-2104 N-[2-fluoro-3-[4-(2-methoxyethylamino)-7H-pyrrolo[2,3-d]pyrimidine-5- carbonyl]phenyl]pyrrolidinc-1-sulfonamide

463.2 P-2105 N-[2-fluoro-3-[4-(3-methoxypropylamino)-7H-pyrrolo[2,3-d]pyrimidine-5- carbonyl]phenyl]pyrrolidine-1-sulfonamide

477.1 P-2106 N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-thiazol-4-yl]-2-fluoro-phenyl]butane- 2-sulfonamide

P-2107 methyl 2-[[5-[2-fluoro-3-(pyrrolidin-1-ylsulfonylamino)benzoyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-4-methyl- pentanoate

533.2 P-2108 N-[2-fluoro-3-[4-[(3-hydroxy-3-methyl-butyl)amino]-7H-pyrrolo[2,3-d]pyrimidine5-carbonyl]phenyl]pyrrolidine-1- sulfonamide

491.2 P-2109 2-[[5-[2-fluoro-3-(pyrrolidin-1-ylsulfonylamino)benzoyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]amino]aceticacid

463.0 P-2110 N-[2-fluoro-3-[4-(2- morpholinoethylamino)-7H-pyrrolo[2,3-d]pyrimidine-5- carbonyl]phenyl]pyrrolidine-1-sulfonamide

518.1 P-2111 N-[2-fluoro-3-[4-(3- morpholinopropylamino)-7H-pyrrolo[2,3-d]pyrimidine-5- carbonyl]phenyl]pyrrolidine-1-sulfonamide

532.1 P-2112 N-[2-fluoro-3-[4-(3,3,3-trifluoropropylamino)-7H-pyrrolo[2,3- d]pyrimidine-5-carbonyl]phenyl]pyrrolidine-1-sulfonamide

501.0 P-2113 N-[3-[4-[[3-(dimethylamino)-2,2-dimethyl-propyl]amino]-7H-pyrrolo[2,3- d]pyrimidine-5-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide

518.1 P-2114 N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-thiazol-4-yl]-2-fluoro- phenyl]pyrrolidine-1-sulfonamide

P-2115 5-[3-[[ethyl(methyl)sulfamoyl]amino]-2- fluoro-benzoyl]-4-(3-methoxypropylamino)-7H-pyrrolo[2,3- d]pyrimidine

465.1 P-2116 5-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-4-(3- methoxypropylamino)-7H-pyrrolo[2,3- d]pyrimidine

483.1 P-2117 5-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-4-(isopropylamino)-7H- pyrrolo[2,3-d]pyrimidine

453.0 P-2118 4-[[(1R)-1-cyclopropylethyl]amino]-5-[3-[[ethyl(methyl(sulfamoyl]amino]-2,6- d]fluoro-benzoyl]-7H-pyrrolo[2,3-d]pyrimidine

479.0 P-2119 5-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-4-(tetrahydropyran-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidine

495.3 P-2120 N-[3-[2-tert-butyl-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-4-yl]-2-fluoro- phenyl]pyrrolidine-1-sulfonamide

500.0 P-2121 N-[3-[2-tert-butyl-5-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-4-yl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide

P-2122 N-[3-[2-tert-butyl-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)thiazol-4-yl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide

P-2123 N-[3-[2-tert-butyl-5-(6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)thiazol-4-yl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide

515.1 P-2124 N-[3-[2-tert-butyl-5-(8-methyl-9H-purin-6-yl)thiazol-4-yl]-2-fluoro- phenyl]pyrrolidine-1-sulfonamide

516.3 P-2125 N-[3-[2-tert-buty]-5-(9H-purin-6-yl)thiazol-4-yl]-2-fluoro-phenyl]pyrrolidine-1- sulfonamide

502.2 P-2126 N-[3-[2-tert-butyl-5-(2-methyl-3H-imidazo[4,5-b]pyridin-7-yl)thiazol-4-yl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide

515.1 P-2127 N-[3-(5-bromo-2-tert-butyl-thiazol-4-yl)-2-fluoro-phenyl]pyrrolidine-1-sulfonamide

P-2128 N-(6-acetamido-3-pyridyl)-2,6-difluoro-3-(morpholinosulfonylamino)benzamide

456.3 P-2129 (3R)-N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-thiazol-4-yl]-2-fluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide

495.3 P-2130 (3S)-N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-thiazol-4-yl]-2-fluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide

494.6 P-2131 N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-thiazol-4-yl]-2-fluoro- phenyl]azetidine-1-sulfonamide

P-2132 N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-thiazol-4-yl]-2-fluoro- phenyl]piperidine-1-sulfonamide

P-2133 N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-thiazol-4-yl]-2-fluoro- phenyl]cyclopropanesulfonamide

P-2134 N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-thiazol-4-yl]-2-fluoro- phenyl]cyclobutanesulfonamide

P-2135 N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-thiazol-4-yl]-2-fluoro- phenyl]cyclopentanesulfonamide

P-2136 N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-thiazol-4-yl]-2-fluoro- phenyl]cyclohexanesulfonamide

P-2137 methyl N-[(1S)-2-[[4-[4-[3-(azetidin-1-ylsulfonylamino)-2-fluoro-phenyl]-2-tert-butyl-thiazol-5-yl]pyrimidin-2-yl]amino]-1- methyl-ethyl]carbamate

P-2138 methyl N-[(1S)-2-[[4-[2-tert-butyl-4-[2-fluoro-3-[[(3R)-3-fluoropyrrolidin-1- yl]sulfonylamino]phenyl]thiazol-5-yl]pyrimidin-2-yl]amino]-1-methyl- ethyl]carbamate

609.7 P-2139 methyl N-[(1S)-2-[[4-[2-tert-butyl-4-[2-fluoro-3-[[(3S)-3-fluoropyrrolidin-1- yl]sulfonylamino]phenyl]thiazol-5-yl]pyrimidin-2-yl]amino]-1-methyl- ethyl]carbamate

P-2140 methyl N-[(1S)-2-[[4-[2-tert-butyl-4-[2- fluoro-3-(1-piperidylsulfonylamino)phenyl]thiazol-5-yl]pyrimidin-2-yl]amino]-1-methyl- ethyl]carbamate

P-2141 methyl N-[(1S)-2-[[4-[2-tert-butyl-4-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-phenyl]thiazol-5-yl]pyrimidin-2-yl]amino]- 1-methyl-ethyl]carbamate

P-2142 methyl N-[(1S)-2-[[4-[2-tert-butyl-4-[3-(cyclopropylsulfonylamino)-2-fluoro-phenyl]thiazol-5-yl]pyrimidin-2-yl]amino]- 1-methyl-ethyl]carbamate

P-2143 methyl N-[(1S)-2-[[4-[2-tert-butyl-4-[3-(cyclobutylsulfonylamino)-2-fluoro-phenyl]thiazol-5-yl]pyrimidin-2-yl]amino]- 1-methyl-ethyl]carbamate

P-2144 methyl N-[(1S)-2-[[4-[2-tert-butyl-4-[3-(cyclopentylsulfonylamino)-2-fluoro-phenyl]thiazol-5-yl]pyrimidin-2-yl]amino]- 1-methyl-ethyl]carbamate

P-2145 methyl N-[(1S)-2-[[4-[2-tert-butyl-4-[3-(cyclohexylsulfonylamino)-2-fluoro-phenyl]thiazol-5-yl]pyrimidin-2-yl]amino]- 1-methyl-ethyl]carbamate

P-2146 N-[3-[5-(2-aminopyrimidin-4-yl)-2-phenyl-thiazol-4-yl]-2-fluoro-phenyl]pyrrolidine-1- sulfonamide

P-2147 (3S)-N-[3-[5-(2-aminopyrimidin-4-yl)-2-phenyl-thiazol-4-yl]-2-fluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide

P-2148 N-[3-[5-(2-aminopyrimidin-4-yl)-2-phenyl-thiazol-4-yl]-2-fluoro-phenyl]piperidine-1- sulfonamide

P-2149 N-[3-[5-(2-aminopyrimidin-4-yl)-2-phenyl- thiazol-4-yl]-2-fluoro-phenyl]cyclopentanesulfonamide

P-2150 N-[3-[5-(2-aminopyrimidin-4-yl)-2-phenyl- thiazol-4-yl]-2-fluoro-phenyl]cyclohexanesulfonamide

P-2151 methyl N-[(1S)-2-[[4-[4-[3-(azetidin-1-ylsulfonylamino)-2-fluoro-phenyl]-2-phenyl-thiazol-5-yl]pyrimidin-2-yl]amino]- 1-methyl-ethyl]carbamate

P-2152 methyl N-[(1S)-2-[[4-[4-[2-fluoro-3-[[(3R)- 3-fluoropyrrolidin-1-yl]sulfonylamino]phenyl]-2-phenyl-thiazol-5-yl]pyrimidin-2-yl]amino]-1-methyl- ethyl]carbamate

629.7 P-2153 methyl N-[(1S)-2-[[4-[4-[2-fluoro-3-[[(3S)-3-fluoropyrrolidin-1- yl]sulfonylamino]phenyl]-2-phenyl-thiazol-5-yl]pyrimidin-2-yl]amino]-1-methyl- ethyl]carbamate

629.7 P-2154 methyl N-[(1S)-2-[[4-[4-[2-fluoro-3-(1-piperidylsulfonylamino)phenyl]-2-phenyl-thiazol-5-yl]pyrimidin-2-yl]amino]-1- methyl-ethyl]carbamate

P-2155 methyl N-[(1S)-2-[[4-[4-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-phenyl]-2-phenyl-thiazol-5-yl]pyrimidin-2-yl]amino]-1-methyl-ethyl]carbamate

P-2156 methyl N-[(1S)-2-[[4-[4-[3- (cyclopropylsulfonylamino)-2-fluoro-phenyl]-2-phenyl-thiazol-5-yl]pyrimidin-2-yl]amino]-1-methyl-ethyl]carbamate

P-2157 methyl N-[(1S)-2-[[4-[4-[3- (cyclobutylsulfonylamino)-2-fluoro-phenyl]-2-phenyl-thiazol-5-yl]pyrimidin-2-yl]amino]-1-methyl-ethyl]carbamate

P-2158 methyl N-[(1S)-2-[[4-[4-[3- (cyclopentylsulfonylamino)-2-fluoro-phenyl]-2-phenyl-thiazol-5-yl]pyrimidin-2-yl]amino]-1-methyl-ethyl]carbamate

P-2159 methyl N-[(1S)-2-[[4-[4-[3- (cyclohexylsulfonylamino)-2-fluoro-phenyl]-2-phenyl-thiazol-5-yl]pyrimidin-2-yl]amino]-1-methyl-ethyl]carbamate

P-2160 methyl N-[(1S)-2-[[4-[4-[5-chloro-2-fluoro-3-(pyrrolidin-1-ylsulfonylamino)phenyl]-1-isopropyl-pyrazol-3-yl]pyrimidin-2- yl]amino]-1-methyl-ethyl]carbamate

595.1 P-2161 methyl N-[(1S)-2-[[4-[4-[5-chloro-2-fluoro-3-[[(3R)-3-fluoropyrrolidin-1- yl]sulfonylamino]phenyl]-1-isopropyl-pyrazol-3-yl]pyrimidin-2-yl]amino]-1- methyl-ethyl]carbamate

613.1 P-2162 methyl N-[(1S)-2-[[4-[4-[5-chloro-2-fluoro-3-[[(3S)-3-fluoropyrrolidin-1- yl]sulfonylamino]phenyl]-1-isopropyl-pyrazol-3-yl]pyrimidin-2-yl]amino]-1- methyl-ethyl]carbamate

P-2163 methyl N-[(1S)-2-[[4-[4-[3-(azetidin-1-ylsulfonylamino)-5-chloro-2-fluoro- phenyl]-1-isopropyl-pyrazol-3-yl]pyrimidin-2-yl]amino]-1-methyl- ethyl]carbamate

581.1 P-2164 methyl N-[(1S)-2-[[4-[4-[5-chloro-3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro- phenyl]-1-isopropyl-pyrazol-3-yl]pyrimidin-2-yl]amino]-1-methyl- ethyl]carbamate

583.1 P-2165 methyl N-[(1S)-2-[[4-[4-[5-chloro-3-(diethylsulfamoylamino)-2-fluoro-phenyl]-1-isopropyl-pyrazol-3-yl]pyrimidin-2- yl]amino]-1-methyl-ethyl]carbamate

597.1 P-2166 methyl N-[(1S)-2-[[4-[4-[5-chloro-3-(dimethylsulfamoylamino)-2-fluoro- phenyl]-1-isopropyl-pyrazol-3-yl]pyrimidin-2-yl]amino]-1-methyl- ethyl]carbamate

569.1 P-2167 methyl N-[(1S)-2-[[4-[4-[5-chloro-3-(cyclohexylsulfonylamino)-2-fluoro- phenyl]-1-isopropyl-pyrazol-3-yl]pyrimidin-2-yl]amino]-1-methyl- ethyl]carbamate

P-2168 methyl N-[(1S)-2-[[4-[4-[5-chloro-3-(cyclopentylsulfonylamino)-2-fluoro- phenyl]-1-isopropyl-pyrazol-3-yl]pyrimidin-2-yl]amino]-1-methyl- ethyl]carbamate

P-2169 methyl N-[(1S)-2-[[4-[4-[5-chloro-3-(cyclobutylsulfonylamino)-2-fluoro- phenyl]-1-isopropyl-pyrazol-3-yl]pyrimidin-2-yl]amino]-1-methyl- ethyl]carbamate

580.1 P-2170 methyl N-[(1S)-2-[[4-[4-[5-chloro-3-(cyclopropylsulfonylamino)-2-fluoro- phenyl]-1-isopropyl-pyrazol-3-yl]pyrimidin-2-yl]amino]-1-methyl- ethyl]carbamate

566.0 P-2181 methyl N-[(1S)-2-[[4-[3-[5-chloro-2-fluoro-3-(1-piperidylsulfonylamino)phenyl]-1-isopropyl-pyrazol-4-yl]pyrimidin-2- yl]amino]-1-methyl-ethyl]carbamate

609.1 The asterisk * in Table 1 indicates the observed MS (ESI) [M −H⁺]⁻molecular weights.

Some embodiments described herein provide a compound as set forth inTable 2 or a pharmaceutically acceptable salt, hydrate, solvate,isomers, tautomers or deuterated analogs thereof.

TABLE 2 Com- MS(ESI) pound [M + H⁺]⁺ No. Name Structure observed P-2171N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,5-difluoro-phenyl]pyrrolidine-1- sulfonamide

525.3 P-2172 (3R)-N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,5-difluoro-phenyl]-3-fluoro- pyrrolidine-1-sulfonamide

543.3 P-2173 5-(2-cyclopropylpyrimidin-5-yl)-3-[3-(dimethylsulfamoylamino)-2,5-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine

499.3 P-2174 (3R)-N-[5-chloro-3-[5-(2- cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]-3-fluoro-pyrrolidine-1- sulfonamide

559.2 P-2175 3-[5-chloro-3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-5-(2- cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine

515.2 P-2176 N-[5-chloro-3-[5-(2- cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]-2,2,5,5-tetradeuterio- pyrrolidine-1-sulfonamide

545.1 P-2177 N-[5-chloro-3-[5-(2- cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2- fluoro-phenyl]-2,2,3,3,4,4,5,5-octadeuterio-pyrrolidine-1-sulfonamide

549.0 P-2178 (3R)-N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3- carbonyl]-2-fluoro-5-(trifluoromethyl)phenyl]-3-fluoro- pyrrolidine-1-sulfonamide

593.1 P-2179 N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2- fluoro-5-(trifluoromethyl)phenyl]pyrrolidine-1- sulfonamide

575.1 P-2180 N-(5-chloro-3-(5-(2- cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluorophenyl)pyrrolidine-1-sulfonamide

540.9 P-2182 (3R)-N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3- carbonyl]-2-fluoro-5-methyl-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide

538.6 P-2183 N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-5-methyl-phenyl]pyrrolidine-2- sulfonamide

520.6

IV. Methods

In another aspect, the present disclosure provides a method forregulating or modulating a MAPK pathway signaling. The method includesselectively inhibiting the MAPK pathway in a first cell having a mutantRAF kinase with a compound of formula (I) or a compound of any of thesubgeneric formulas of formula (I), or a compound as described herein,or a pharmaceutically acceptable salt or a solvate or hydrate thereof,or a composition comprising a compound of formula (I′) or (I) or acompound of any of the subgeneric formulas of formula (I), for example,formulas (Ia), (Ia-1), (Ia-2), (Ib), (Ib-1), (Ib-2), (Ib-1a), (Ib-1b),(Ic), (Ic-1), (Ic-1a), (Ic-2), (Ic-2a), (Id), (Id-1), (Id-1a), (Id-2),(Id-2a), (Ie), (Ie-1), (Ie-1a), (Ie-2), (Ie-2a), (If), (If-1), (If-2),(If-3), (If-4), (Ig), (Ig-1), (Ig-2), (Ig-3), (Ig-4), (Ih), (Ih-1),(Ih-2), (Ih-3), (Ih-4), (Ij), (Ij-1) or (Ij-2), or any of the compoundsdescribed herein, or a pharmaceutically acceptable salt or a solvate orhydrate thereof, wherein the compound does not induce the activation ofthe MAPK pathway in a second cell. In some embodiments, the selectivelyinhibiting comprises selectively inhibiting a mutant Raf kinase in afirst cell. In some embodiments, the mutant RAF kinase is a mutant A-rafkinase, a mutant BRAF kinase, a mutant c-Raf kinase or combinationsthereof. In one embodiment, the mutant RAD kinase is a mutant BRAFkinase. In certain embodiments, the mutant Raf kinase is mutant BRAFkinase. In one embodiment, the regulating, modulating or inhibiting of aMAPK pathway signaling can be achieved through regulating theinteraction of a BRAF kinase inhibitor as described herein with theLeucine 505 amino acid residue in the C-terminal end of an αC helix,such that there is no activation of MAPK pathway in a second cell asdetermined by monitoring the levels of pERK and/or pMEK. In oneinstance, the BRAF inhibitor is in direct contact with the Leucine 505amino acid residue in the C-terminal end of an αC helix. In someembodiments, the second cell has RAS mutation or upstream receptortyrosine kinase activation. In some embodiments, the disclosure providescontacting a cell having a mutant BRAF kinase with a BRAF inhibitor. Inone embodiment, the regulating, modulating or inhibiting of a MAPKpathway signaling can be achieved through regulating the interaction ofa BRAF kinase inhibitor as described herein with the Leucine 505 aminoacid residue in the C-terminal end of an αC helix, such that there is noactivation of pERK kinase.

In some embodiments of the methods provided herein, the RAF inhibitor,e.g., a BRAF inhibitor is a molecule/compound containing asulfamoylamino group having the formula:

wherein R¹, R² and R³ are as defined in any embodiments of compounds offormula (I) or any subgeneric formulas of formula (I). In certainembodiments, R¹ and R² are each independently optionally substitutedalkyl, aryl, heteroaryl, cycloalkyl or R¹ and R² taken together to forma optionally substituted 5- or 6-membered heterocycloalkyl ring havingfrom 0-1 heteroatoms selected from O, N or S; R³ is H or C₁₋₆alkyl; andthe wavy line indicates the point of attachment to the rest of themolecule. In certain embodiments, the BRAF inhibitor is a compoundhaving formula (I′):

where the variables Z, L¹, E, L², R³ and Y are as defined in anyembodiments of compounds of formula (I) and subgeneric formulas offormula (I) as described herein. In one embodiment, Y is —N(R¹)(R²). Inanother embodiment, Y is —C(R⁸)(R⁹)(R¹⁰). In one embodiment, R³ is H. Inanother embodiment, R¹ is methyl and R² is ethyl. In other embodiments,R¹ and R² taken together with the nitrogen atom to which they areattached form an optionally substituted 5-membered heterocycloalkylring.

In some embodiments of the methods provided herein, the BRAF inhibitoris a compound of formula (I′) or (I) or a compound of any of thesubgeneric formulas of formula (I), or a compound as described herein,or a pharmaceutically acceptable salt or a solvate or hydrate thereof,or a composition comprising a compound of formula (I) or (I′) or acompound of any of the subgeneric formulas of formula (I), for example,formulas (Ia), (Ia-1), (Ia-2), (Ib), (Ib-1), (Ib-2), (Ib-1a), (Ib-1b),(Ic), (Ic-1), (Ic-1a), (Ic-2), (Ic-2a), (Id), (Id-1), (Id-1a), (Id-2),(Id-2a), (Ie), (Ie-1), (Ie-1a), (Ie-2), (Ie-2a), (If), (If-1), (If-2),(If-3), (If-4), (Ig), (Ig-1), (Ig-2), (Ig-3), (Ig-4), (Ih), (Ih-1),(Ih-2), (Ih-3), (Ih-4), (Ij), (Ij-1) or (Ij-2) or any of the compoundsdescribed herein, or a pharmaceutically acceptable salt or a solvate orhydrate thereof.

In some embodiments of the methods provided herein, the inhibitioninvolves regulating the interaction of the —N(R¹)(R²) or —C(R⁸)(R⁹)(R¹⁰)group of the BRAF kinase inhibitor with the Leucine 505 amino acidresidue in the C-terminal end of an αC helix, wherein the wavy lineindicates the point of attachment to the rest of the molecule. In oneembodiment, the BRAF inhibitor is in direct contact with the Leucine 505amino acid residue in the C-terminal end of an αC helix.

The cell can have RAS mutation or upstream receptor tyrosine kinaseactivation. In the methods provided herein, the inhibition of the mutantBRAF kinase does not activate the MAPK pathway in cells having RASmutation or upstream receptor tyrosine kinase activation.

In some embodiments of the methods provided herein, the BRAF inhibitoris a compound listed in Table A.

TABLE AN-[3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide (P-0012);5-chloro-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine(P-0013);5-(4-chlorophenyl)-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0014);3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0015);N-[2,4-difluoro-3-(5-fluoro-4-iodo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl]pyrrolidine-1-sulfonamide (P-0016);N-[3-[4-(cyclopropylmethylamino)-5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide (P-0017);5-cyano-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine(P-0018);5-chloro-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine(P-0019);5-(4-chlorophenyl)-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine(P-0020);3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0021);N-[3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide (P-0022);N-[3-[5-[2-(dimethylamino)pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide (P-0023);N-[2-fluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl]pyrrolidine-1-sulfonamide(P-0024);N-[2,4-difluoro-3-(5-iodo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl]pyrrolidine-1-sulfonamide(P-0025);3-[3-[[cyclopropyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0026);[2-fluoro-3-(methylsulfamoylamino)phenyl]-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone (P-0027);5-(4-cyanophenyl)-3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine(P-0028);3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-5-(3-pyridyl)-1H-pyrrolo[2,3-b]pyridine(P-0029);3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-5-(6-methyl-3-pyridyl)-1H-pyrrolo[2,3-b]pyridine(P-0030);5-[6-(dimethylamino)-3-pyridyl]-3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0031);5-(4-cyanophenyl)-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine(P-0032);3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(3-pyridyl)-1H-pyrrolo[2,3-b]pyridine(P-0033);3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(6-methyl-3-pyridyl)-1H-pyrrolo[2,3-b]pyridine (P-0034);3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine(P-0035);3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-5-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine;3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-phenyl-1H-pyrrolo[2,3-b]pyridine(P-0036);3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-5-phenyl-1H-pyrrolo[2,3-b]pyridine(P-0037);5-bromo-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine(P-0038);5-cyano-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine(P-0039);3-[2-fluoro-3-[[methyl(propyl)sulfamoyl]amino]benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0040);3-benzyloxy-N-[2-fluoro-3-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0041);1-cyclopropyl-N-[2-fluoro-3-[5-(1-methylpyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]methanesulfonamide (P-0042);N-[2-fluoro-3-[5-(3-pyridyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide(P-0043);N-[3-[5-(2,4-dimethoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide (P-0044);N-[2-fluoro-3-[5-(6-methyl-3-pyridyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0045);N-[3-[5-[6-(dimethylamino)-3-pyridyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide (P-0046);N-[2-fluoro-3-[5-(2-isopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0047);N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide (P-0048);N-[3-[5-(4-cyano-3-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide (P-0049);N-[3-[5-[4-(1-cyanocyclopropyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide (P-0050);3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-5-(2-isopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0051);5-(2-cyclopropylpyrimidin-5-yl)-3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0052);3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-5-[6-(trifluoromethyl)-3-pyridyl]-1H-pyrrolo[2,3-b]pyridine (P-0053);5-(4-cyano-3-methoxy-phenyl)-3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0054);5-[4-(1-cyanocyclopropyl)phenyl]-3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0055);3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0056);3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(2-isopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0057);5-(2-cyclopropylpyrimidin-5-yl)-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0058);3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-[6-(trifluoromethyl)-3-pyridyl]-1H-pyrrolo[2,3-b]pyridine (P-0059);5-(4-cyano-3-methoxy-phenyl)-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H- pyrrolo[2,3-b]pyridine (P-0060);5-[4-(1-cyanocyclopropyl)phenyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0061);N-[2-fluoro-3-[5-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0062);N-[2-fluoro-3-(5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl]pyrrolidine-1-sulfonamide(P-0063);5-[2-(cyclopropylamino)pyrimidin-5-yl]-3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0064);N-[2-fluoro-3-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]-2-methoxy-ethanesulfonamide (P-0065); methyl3-[[2-fluoro-3-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]sulfamoyl]propanoate (P-0066);N-[2-fluoro-3-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]cyclopropanesulfonamide (P-0067);[3-(ethylsulfamoylamino)-2-fluoro-phenyl]-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone (P-0068);[3-(ethylsulfamoylamino)-2-fluoro-phenyl]-(5-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone(P-0069);3-[2-fluoro-3-[[isobutyl(methyl)sulfamoyl]amino]benzoyl]-5-iodo-1H-pyrrolo[2,3-b]pyridine(P-0070);[2-fluoro-3-(isopropylsulfamoylamino)phenyl]-(5-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone(P-0071);3-[2-fluoro-3-[[isobutyl(methyl)sulfamoyl]amino]benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0072);3-[2-fluoro-3-[[2-methoxyethyl(methyl)sulfamoyl]amino]benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0073);N-[2-fluoro-3-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]-2-methyl-pyrrolidine-1-sulfonamide (P-0074);3-[2-fluoro-3-[[isopropyl(methyl)sulfamoyl]amino]benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0075);5-[6-(dimethylamino)-3-pyridyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0076);5-[2-(cyclopropylamino)pyrimidin-5-yl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0077);5-(2-cyclopropylpyrimidin-5-yl)-3-[2,6-difluoro-3-[[methyl(propyl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0078);5-[4-(1-cyanocyclopropyl)phenyl]-3-[2,6-difluoro-3-[[methyl(propyl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0079);5-[4-(1-cyanocyclopropyl)phenyl]-3-[2-fluoro-3-[[2-methoxyethyl(methyl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0080);5-[2-(cyclopropylamino)pyrimidin-5-yl]-3-[2-fluoro-3-[[2-methoxyethyl(methyl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine(P-0081);5-[2-(cyclopropylamino)pyrimidin-5-yl]-3-[2-fluoro-3-[[methyl(propyl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0082);3-[3-[[cyclopropylmethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0083);3-[3-[[cyclopropylmethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0084);5-(2-cyclopropylpyrimidin-5-yl)-3-[2-fluoro-3-[[2-methoxyethyl(methyl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0085);5-(2-cyclopropylpyrimidin-5-yl)-3-[2-fluoro-3-[[methyl(propyl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0086);5-(6-cyclopropyl-3-pyridyl)-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0087);3,3-difluoro-N-[2-fluoro-3-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]azetidine-1-sulfonamide (P-0088);4-[[(1S)-1-cyclopropylethyl]amino]-5-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-7H-pyrrolo[2,3-d]pyrimidine (P-0089);N-[3-[5-(4-cyanophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide (P-0090);N-[3-[5-(2-cyanopyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide (P-0091);N-[2-fluoro-3-[5-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0092);N-[3-[5-(5-cyano-3-pyridyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide (P-0093);N-[2-fluoro-3-[5-[6-(trifluoromethyl)-3-pyridyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0095);5-(2-cyanopyrimidin-5-yl)-3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0096);3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-5-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0097);5-(5-cyano-3-pyridyl)-3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine(P-0098);5-(6-cyano-3-pyridyl)-3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine(P-0099);5-(2-cyanopyrimidin-5-yl)-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0100);5-(5-cyano-3-pyridyl)-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0101);5-(6-cyano-3-pyridyl)-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0102);3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-5-[4-(1-hydroxy-1-methyl-ethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine (P-0103);3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-[4-(1-hydroxy-1-methyl-ethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine (P-0104);N-[2-fluoro-3-[5-[4-(1-hydroxy-1-methyl-ethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0105);5-[2-(dimethylamino)pyrimidin-5-yl]-3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0106);3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-5-(2-pyrrolidin-1-ylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0107);3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(2-pyrrolidin-1-ylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0108);N-[2-fluoro-3-[5-(2-pyrrolidin-1-ylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0109);3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-5-iodo-1H-pyrrolo[2,3-b]pyridine(P-0110);3-[2-fluoro-3-[[methyl(propyl)sulfamoyl]amino]benzoyl]-5-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0111);3-[3-[[cyclopropylmethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0112);5-(6-cyclopropyl-3-pyridyl)-3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0113);5-(6-cyclopropyl-3-pyridyl)-3-[2-fluoro-3-[[methyl(propyl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0114);3-[3-[[cyclopropylmethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(6-cyclopropyl-3-pyridyl)-1H-pyrrolo[2,3-b]pyridine (P-0115);3-[2,6-difluoro-3-[[methyl(propyl)sulfamoyl]amino]benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0116);[2-fluoro-3-(propylsulfamoylamino)phenyl]-(5-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone(P-0117);[2-fluoro-3-(propylsulfamoylamino)phenyl]-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone(P-0223);N-[2-fluoro-3-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]butane-2-sulfonamide (P-0024);N-[2-fluoro-3-[5-(2-pyrrolidin-1-ylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]butane-2-sulfonamide (P-0225);N-[3-[5-[2-(cyclopropylamino)pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]butane-2-sulfonamide (P-0226);N-[3-[5-[4-(1-cyanocyclopropyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]butane-2-sulfonamide (P-00227);N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]butane-2-sulfonamide (P-0228);N-[2-fluoro-3-[5-(2-isopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]butane-2-sulfonamide (P-0229);N-[3-[5-[6-(dimethylamino)-3-pyridyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]butane-2-sulfonamide (P-0230);N-[2-fluoro-3-[5-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]butane-2-sulfonamide (P-0231);N-[3-[5-[2-(cyclopropylamino)pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide (P-0232);5-(2-cyclopropylpyrimidin-5-yl)-3-[2-fluoro-3-[[isopropyl(methyl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0233);N-[2-fluoro-3-[5-(2-morpholinopyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide; (P-0235);N-[2-fluoro-3-[5-(2-morpholinopyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]butane-2-sulfonamide (P-0236);5-[4-(1-cyanocyclopropyl)phenyl]-3-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0237);5-(2-cyclopropylpyrimidin-5-yl)-3-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0238);5-[4-(1-cyanocyclopropyl)phenyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0239);5-(2-cyclopropylpyrimidin-5-yl)-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0240);N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide (P-0241);[2-fluoro-3-(propylsulfamoylamino)phenyl]-[5-(1-methylpyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone (P-0242);1-[4-[3-[2-fluoro-3-(pyrrolidin-1-ylsulfonylamino)benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]cyclopropanecarboxylic acid (P-0243);3-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-5-(5-ethoxypyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridine (P-0244);5-[4-(1-cyano-1-methyl-ethyl)phenyl]-3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0245);N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]-3,3-dimethyl-pyrrolidine-1-sulfonamide (P-0246);N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]-3-methyl-pyrrolidine-1-sulfonamide (P-0247);N-[3-[5-[4-(1-cyanocyclopropyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide (P-0248);3-[3-[[cyclopropyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0249);[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-[2-fluoro-3-(propylsulfamoylamino)phenyl]methanone (P-0251);3-[3-[[cyclopropyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0252);1-[4-[3-[2-fluoro-3-(pyrrolidin-1-ylsulfonylamino)benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]cyclopropanecarboxamide (P-0253); methyl1-[4-[3-[2-fluoro-3-(pyrrolidin-1-ylsulfonylamino)benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]cyclopropanecarboxylate (P-0254);5-[4-(1-cyano-1-methyl-ethyl)phenyl]-3-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0255);5-(2-ethoxypyrimidin-5-yl)-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0256); ethyl1-[[2-fluoro-3-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]sulfamoyl]pyrrolidine-2-carboxylate (P-0257);4-[5-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]pyrimidin-2-yl]morpholine (P-0258);4-[3-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]morpholine (P-0259);N-[2,4-difluoro-3-[5-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0260);N-[2,4-difluoro-3-[5-(2-piperazin-1-ylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0261);N-[2,4-difluoro-3-[5-[2-(4-hydroxy-1-piperidyl)pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0262);3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine (P-0263); tert-butyl4-[5-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]pyrimidin-2-yl]piperazine-1-carboxylate (P-0264);N-[2,4-difluoro-3-[5-[2-(1-hydroxy-1-methyl-ethyl)thiazol-4-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0265);N-[2,4-difluoro-3-[5-(2-morpholinopyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0266);N-[1-[[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]sulfamoyl]pyrrolidin-3-yl]-N-methyl-acetamide (P-0267);3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(2-piperazin-1-ylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0268);N-[3-[5-[2-(azetidin-1-yl)pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide (P-0269);N-[2,4-difluoro-3-[5-(2-methoxythiazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0270);(3R)-N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]-3-methyl-pyrrolidine-1-sulfonamide (P-0271);N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]-3-(methylamino)pyrrolidine-1-sulfonamide (P-0272);N-[2,4-difluoro-3-[5-(4-pyridyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0273);N-[3-(5-cyclopropyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]pyrrolidine-1-sulfonamide (P-0274);3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[2-(4-hydroxy-1-piperidyl)pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine (P-0275);5-[3-(1-cyanocyclopropyl)phenyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0276);5-[2-(azetidin-1-yl)pyrimidin-5-yl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0277);N-[3-[5-(2-aminopyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide (P-0279);N-[3-[5-(2-aminopyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide (P-0280);N-[2-fluoro-3-[5-(4-pyridyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide(P-0281);N-[2,4-difluoro-3-[5-(2-morpholinopyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0282);3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(2-fluoro-4-pyridyl)-1H-pyrrolo[2,3-b]pyridine (P-0283);N-[2,4-difluoro-3-[5-(2-morpholino-4-pyridyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0284);N-[2,4-difluoro-3-[5-[2-(4-methylpiperazin-1-yl)-4-pyridyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0285);N-[3-[5-[2-(cyclobutoxy)-4-pyridyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide (P-0286);N-[2,4-difluoro-3-[5-(2-methoxy-4-pyridyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0287);N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3,3-difluoro-pyrrolidine-1-sulfonamide (P-0288);(3S)-N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (P-0289); methyl2-[[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]sulfamoyl]propanoate (P-0291);5-[2-(dimethylamino)pyrimidin-5-yl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0292);3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(2-pyrrolidin-1-ylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0293);N-[2,4-difluoro-3-[5-[6-(trifluoromethyl)pyrimidin-4-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0294);N-[3-[5-(2-cyclopropyl-4-pyridyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide (P-0295);5-cyclobutyl-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine(P-0297);5-cyclopropyl-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine(P-0298);N-[3-[5-(6-aminopyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide (P-0299);5-(4-cyanophenyl)-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0300);3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[4-(trifluoromethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine (P-0301);5-[3-(dimethylamino)phenyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0302);3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(4-pyrrolidin-1-ylphenyl)-1H-pyrrolo[2,3-b]pyridine (P-0303);2-[4-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]-5-methyl-1,3,4-oxadiazole (P-0304);2-[4-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]-5-(methylamino)-1,3,4-thiadiazole (P-0305);3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[5-(1-hydroxy-1-methyl-ethyl)-3-pyridyl]-1H-pyrrolo[2,3-b]pyridine (P-0306);3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[6-(1-hydroxy-1-methyl-ethyl)-3-pyridyl]-1H-pyrrolo[2,3-b]pyridine (P-0307);5-[4-(diethylamino)phenyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0308);3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(2-oxoindolin-6-yl)-1H-pyrrolo[2,3-b]pyridine (P-0309);3-[5-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-thienyl]-5-methyl-1,2,4-oxadiazole (P-0310);2-amino-6-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]quinazoline (P-0311);N-cyclopropyl-5-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]pyridine-2-carboxamide (P-0312);2-(dimethylamino)-6-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]quinazoline (P-0313);3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[4-(1-hydroxycyclopropyl)phenyl]-1H-pyrrolo[2,3-b]pyridine (P-0314);5-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]thiazole(P-0315);4-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-(1-hydroxy-1-methyl-ethyl)thiazole (P-0316);3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(6-methoxypyridazin-3-yl)-1H-pyrrolo[2,3-b]pyridine (P-0317);N-[2,4-difluoro-3-[5-(6-morpholinopyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0318);N-[2,4-difluoro-3-[5-[6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0319);(3S)-N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-methyl-pyrrolidine-1-sulfonamide (P-0320);N-[2-fluoro-3-[5-(6-morpholinopyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0321);N-[2-fluoro-3-[5-[6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0322);N-[2-fluoro-3-[5-[6-(4-methylpiperazin-1-yl)-2-pyridyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0324);N-[2-fluoro-3-[5-(4-methoxypyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0325);N-[2-fluoro-3-[5-(4-methylpyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0326);(3R)-N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (P-0327);[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-[2,6-difluoro-3-(methylsulfamoylamino)phenyl]methanone (P-0334);[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-[3-(ethylsulfamoylamino)-2,6-difluoro-phenyl]methanone (P-0335);5-(2-cyclopropylpyrimidin-5-yl)-3-[2,6-difluoro-3-(sulfamoylamino)benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0336);N-[3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]butane-2-sulfonamide (P-0337);(3R)-N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (P-0338);N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (P-0339);5-(2-cyclopropylpyrimidin-5-yl)-3-[2,6-difluoro-3-[[methyl(2,2,2-trifluoroethyl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine(P-0340);N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]butane-2-sulfonamide (P-0342);5-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-methoxy-thiazole (P-0343);3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(1H-indazol-6-yl)-1H-pyrrolo[2,3-b]pyridine (P-0344);N-[2,4-difluoro-3-[5-(2-pyrrolidin-1-ylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0345);N-[3-(5-cyclobutyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]pyrrolidine-1-sulfonamide(P-0346);N-[2-fluoro-3-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]cyclopropanesulfonamide (P-0347);1-allyl-N-[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]cyclopropanesulfonamide (P-0348);N-[2,4-difluoro-3-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]cyclopropanesulfonamide (P-0349);N-[2,4-difluoro-3-[5-(5-methoxy-3-pyridyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]cyclopropanesulfonamide (P-0350); andN-[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]cyclopropanesulfonamide(P-0351);5-(2-aminopyrimidin-4-yl)-2-tert-butyl-4-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-phenyl]thiazole(P-0352);or pharmaceutically acceptable salts, hydrates, solvates, tautomers orisomers thereof. In some embodiments, the methods provide the aboveselected compounds and pharmaceutically acceptable salts thereof. Inother embodiments, the methods provide the above selected compounds andpharmaceutically acceptable salts and tautomers and isomers thereof.

In some embodiments of the methods provided herein, the BRAF inhibitoris a compound listed in Table B.

TABLE B Compound Name No. (MS(ESI) [M + H⁺]⁺) P-0118[2-fluoro-3-(phenylsulfamoylamino)phenyl]-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone (519.1) P-01193-[2-fluoro-3-[[methyl(phenyl)sulfamoyl]amino]benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (533.1) P-0120[2-fluoro-3-(3-pyridylsulfamoylamino)phenyl]-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone (520.1) P-01213-[2-fluoro-3-[[methyl(3-pyridyl)sulfamoyl]amino]benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (534.1) P-0122[2-fluoro-3-(thiazol-5-ylsulfamoylamino)phenyl]-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone (526.1) P-01235-[[2-fluoro-3-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]sulfamoyl-methyl-amino]thiazole (540.1) P-0124[3-(cyclopentylsulfamoylamino)-2-fluoro-phenyl]-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone (511.1) P-01253-[3-[[cyclopentyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (525.2) P-0126[3-(cyclopropylsulfamoylamino)-2-fluoro-phenyl]-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone (483.1) P-0127[2-fluoro-3-(tetrahydropyran-4-ylsulfamoylamino)phenyl]-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone (527.1) P-01283-[2-fluoro-3-[[methyl(tetrahydropyran-4-yl)sulfamoyl]amino]benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (541.2) P-01293-[2-fluoro-3-[[2-fluoroethyl(methyl)sulfamoyl]amino]benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (503.1) P-01303-[2-fluoro-3-[[methyl(2,2,2-trifluoroethyl)sulfamoyl]amino]benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (539.1) P-01313-[2-fluoro-3-[[3-fluoropropyl(methyl)sulfamoyl]amino]benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (517.1) P-01325-chloro-3-[2-fluoro-3-[[2-methoxyethyl(methyl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (441.1) P-01335-chloro-3-[2-fluoro-3-[[3-fluoropropyl(methyl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (443.1) P-01343-[2-fluoro-3-[[3-fluoropropyl(methyl)sulfamoyl]amino]benzoyl]-5-(2-isopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (529.2) P-01353-[2-fluoro-3-[[[1-(methoxymethyl)cyclopropyl]-methyl-sulfamoyl]amino]benzoyl]-5-(2-isopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (553.2) P-01365-chloro-3-[2-fluoro-3-[[[1-(methoxymethyl)cyclopropyl]-methyl-sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (467.1) P-01375-chloro-3-[3-[[2-cyclopropylethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (451.1) P-01383-[3-[[2-cyclopropylethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(2-isopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (537.2) P-01395-chloro-3-[2-fluoro-3-[[[1-(hydroxymethyl)cyclopropyl]methyl-methyl-sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (467.1) P-0140 methyl1-[[[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]sulfamoyl-methyl-amino]methyl]cyclopropanecarboxylate (495.1)P-01415-chloro-3-[3-[[2-cyanoethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (436.1) P-0142(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-[2-fluoro-3-(3-methoxypropylsulfamoylamino)phenyl]methanone (441.1) P-0143N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-4-methyl-piperazine-1-sulfonamide (452.1) P-01445-chloro-3-[2-fluoro-3-[[(2-hydroxy-2-methyl-propyl)-methyl-sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (455.1) P-01455-chloro-3-[2-fluoro-3-[[(2-hydroxy-1,1-dimethyl-ethyl)-methyl-sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (455.1) P-0146N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]azetidine-1-sulfonamide (493.1) P-0147N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]-3-fluoro-azetidine-1-sulfonamide (511.1) P-01485-(2-cyclopropylpyrimidin-5-yl)-3-[2-fluoro-3-[[methyl(oxetan-3-yl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (523.1) P-01493-[3-[[cyclobutyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (521.2) P-01505-chloro-3-[2-fluoro-3-[[methyl(tetrahydrofuran-3-yl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (453.1) P-0151N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-3-methoxy-pyrrolidine-1-sulfonamide (453.1) P-0152N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-3-(methylamino)pyrrolidine-1-sulfonamide (452.1) P-0153N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-3-(dimethylamino)pyrrolidine-1-sulfonamide (466.1) P-0154N-[3-[5-[6-(1-cyanocyclopropyl)-3-pyridyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide (531.2) P-01551-[5-[3-[2-fluoro-3-(pyrrolidin-1-ylsulfonylamino)benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-pyridyl]cyclopropanecarboxamide (549.2) P-01561-[5-[3-[2-fluoro-3-(pyrrolidin-1-ylsulfonylamino)benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-pyridyl]cyclopropanecarboxylic acid (550.2) P-01571-[4-[3-[2-fluoro-3-(pyrrolidin-1-ylsulfonylamino)benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]cyclopropanecarboxamide (548.2) P-01581-[4-[3-[2-fluoro-3-(pyrrolidin-1-ylsulfonylamino)benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]cyclopropanecarboxylic acid (548.2) P-01593-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-5-(5-methoxypyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridine (471.1) P-01605-[5-(dimethylamino)pyrazin-2-yl]-3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (484.2) P-01613-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-5-(6-methoxypyridazin-3-yl)-1H-pyrrolo[2,3-b]pyridine (471.1) P-01624-[5-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]pyrimidin-2-yl]morpholine (540.2) P-01635-chloro-3-[2-fluoro-3-[[(4-fluorophenyl)-methyl-sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (477.1) P-01643-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(1-methylpyrrol-3-yl)-1H-pyrrolo[2,3-b]pyridine (442.1) P-01653-[2-fluoro-3-[[methyl(propyl)sulfamoyl]amino]benzoyl]-5-(1-methylpyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine (471.2) P-01665-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]thiazole (460.1) P-01673-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(1-methylimidazol-4-yl)-1H-pyrrolo[2,3-b]pyridine (457.1) P-01684-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]oxazole (444.1) P-0169[2,6-difluoro-3-(phenylsulfamoylamino)phenyl]-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone (537.1) P-01703-[2,6-difluoro-3-[[methyl(phenyl)sulfamoyl]amino]benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (551.1) P-0171[2,6-difluoro-3-(3-pyridylsulfamoylamino)phenyl]-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone (538.1) P-01723-[2,6-difluoro-3-[[methyl(3-pyridyl)sulfamoyl]amino]benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (552.1) P-0173[2,6-difluoro-3-(thiazol-5-ylsulfamoylamino)phenyl]-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone (544.1) P-01745-[[2,4-difluoro-3-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]sulfamoyl-methyl-amino]thiazole (558.1) P-0175[3-(cyclopentylsulfamoylamino)-2,6-difluoro-phenyl]-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone (529.1) P-01763-[3-[[cyclopentyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (543.2) P-0177[3-(cyclopropylsulfamoylamino)-2,6-difluoro-phenyl]-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone (501.1) P-0178[2,6-difluoro-3-(tetrahydropyran-4-ylsulfamoylamino)phenyl]-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone (545.1)P-01793-[2,6-difluoro-3-[[methyl(tetrahydropyran-4-yl)sulfamoyl]amino]benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (559.1) P-01803-[2,6-difluoro-3-[[2-fluoroethyl(methyl)sulfamoyl]amino]benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (521.1) P-01813-[2,6-difluoro-3-[[methyl(2,2,2-trifluoroethyl)sulfamoyl]amino]benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (556.1) P-01823-[2,6-difluoro-3-[[3-fluoropropyl(methyl)sulfamoyl]amino]benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (534.1) P-01835-chloro-3-[2,6-difluoro-3-[[2-methoxyethyl(methyl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (458.1) P-01845-chloro-3-[2,6-difluoro-3-[[3-fluoropropyl(methyl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (561.1) P-01853-[2,6-difluoro-3-[[3-fluoropropyl(methyl)sulfamoyl]amino]benzoyl]-5-(2-isopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (547.2) P-01863-[2,6-difluoro-3-[[[1-(methoxymethyl)cyclopropyl]-methyl-sulfamoyl]amino]benzoyl]-5-(2-isopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine(571.2) P-01875-chloro-3-[2,6-difluoro-3-[[[1-(methoxymethyl)cyclopropyl]-methyl-sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (485.1) P-01885-chloro-3-[3-[[2-cyclopropylethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (469.1) P-01893-[3-[[2-cyclopropylethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(2-isopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (555.2) P-01905-chloro-3-[2,6-difluoro-3-[[[1-(hydroxymethyl)cyclopropyl]methyl-methyl-sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (485.1) P-0191 methyl1-[[[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]sulfamoyl-methyl-amino]methyl]cyclopropanecarboxylate (513.1)P-01925-chloro-3-[3-[[2-cyanoethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (454.0) P-0193(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-[2,6-difluoro-3-(3-methoxypropylsulfamoylamino)phenyl]methanone (459.1) P-0194N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-methyl-piperazine-1-sulfonamide (470.1) P-01955-chloro-3-[2,6-difluoro-3-[[(2-hydroxy-2-methyl-propyl)-methyl-sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (473.1) P-01965-chloro-3-[2,6-difluoro-3-[[(2-hydroxy-1,1-dimethyl-ethyl)-methyl-sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (473.1) P-0197N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]azetidine-1-sulfonamide (511.1) P-0198N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-azetidine-1-sulfonamide (529.1) P-01995-(2-cyclopropylpyrimidin-5-yl)-3-[2,6-difluoro-3-[[methyl(oxetan-3-yl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (541.1) P-02003-[3-[[cyclobutyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (539.2) P-02015-chloro-3-[2,6-difluoro-3-[[methyl(tetrahydrofuran-3-yl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (471.1) P-0202N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-methoxy-pyrrolidine-1-sulfonamide (471.1) P-0203N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-(methylamino)pyrrolidine-1-sulfonamide (470.1) P-0204N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-(dimethylamino)pyrrolidine-1-sulfonamide (484.1) P-0205N-[3-[5-[6-(1-cyanocyclopropyl)-3-pyridyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide (549.1) P-02061-[5-[3-[2,6-difluoro-3-(pyrrolidin-1-ylsulfonylamino)benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-pyridyl]cyclopropanecarboxamide (567.2) P-02071-[5-[3-[2,6-difluoro-3-(pyrrolidin-1-ylsulfonylamino)benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-pyridyl]cyclopropanecarboxylic acid (568.1) P-02081-[4-[3-[2,6-difluoro-3-(pyrrolidin-1-ylsulfonylamino)benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]cyclopropanecarboxamide (566.2) P-02091-[4-[3-[2,6-difluoro-3-(pyrrolidin-1-ylsulfonylamino)benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]cyclopropanecarboxylic acid (567.1) P-02103-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-5-(5-methoxypyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridine (489.1) P-02115-[5-(dimethylamino)pyrazin-2-yl]-3-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (502.1) P-02123-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-5-(6-methoxypyridazin-3-yl)-1H-pyrrolo[2,3-b]pyridine (489.1) P-02134-[5-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]pyrimidin-2-yl]morpholine (558.2) P-02145-chloro-3-[2,6-difluoro-3-[[(4-fluorophenyl)-methyl-sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (495.0) P-02153-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-5-(1-methylpyrrol-3-yl)-1H-pyrrolo[2,3-b]pyridine (460.1) P-02163-[2,6-difluoro-3-[[methyl(propyl)sulfamoyl]amino]benzoyl]-5-(1-methylpyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine (489.1) P-02175-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]thiazole (478.1) P-02183-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(1-methylimidazol-4-yl)-1H-pyrrolo[2,3-b]pyridine (475.1) P-02194-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]oxazole (462.1) P-02206-[3-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]quinoline (508.1) P-02216-[3-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]quinazoline (509.1) P-02226-[3-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-1,3-benzothiazole (514.1)or pharmaceutically acceptable salts, hydrates, solvates, tautomers orisomers thereof. In some embodiments, the methods provide the aboveselected compounds and pharmaceutically acceptable salts thereof. Inother embodiments, the methods provide the above selected compounds andpharmaceutically acceptable salts and tautomers and isomers thereof.

In another aspect, provided herewith is a method for suppressing orpreventing a MAPK pathway signaling. The method includes contacting amutant BRAF protein kinase in a cell with a BRAF inhibitor; andregulating/modulating the interaction of the BRAF inhibitor Leucine 505amino acid residue in the C-terminal end of an αC helix in the mutantBRAF protein kinase, thereby suppressing or preventing the activation ofMAPK pathway signaling. The activation of MAPK pathway or activation ofpERk can also be suppressed or prevented in cells that have RAS mutationor upstream receptor tyrosine kinase activation.

In some embodiments of methods for suppressing/preventing a MAPK pathwaysignaling provided herein, the BRAF inhibitor is a molecule containing asulfamoylamino group having the formula:

wherein R¹ and R² are each independently optionally substituted alkyl,aryl, heteroaryl, cycloalkyl or R¹ and R² taken together to form aoptionally substituted 5- or 6-membered heterocycloalkyl ring havingfrom 0-1 heteroatoms selected from O, N or S; and R³ is H or C₁₋₆alkyl.In some embodiments, R¹, R² and R³ are as defined in any of theembodiments described herein. In certain embodiments of methods forsuppressing/preventing a MAPK pathway signaling provided herein, theBRAF inhibitor is a compound of formula (I′) or (I) or a compound of anyof the subgeneric formulas of formula (I), or a compound as describedherein, or a pharmaceutically acceptable salt or a solvate or hydratethereof, or a composition comprising a compound of formula (I) or (I′) acompound of any of the subgeneric formulas of formula (I), for example,formulas (Ia), (Ia-1), (Ia-2), (Ib), (Ib-1), (Ib-2), (Ib-1a), (Ib-1b),(Ic), (Ic-1), (Ic-1a), (Ic-2), (Ic-2a), (Id), (Id-1), (Id-1a), (Id-2),(Id-2a), (Ie), (Ie-1), (Ie-1a), (Ie-2), (Ie-2a), (If), (If-1), (If-2),(If-3), (If-4), (Ig), (Ig-1), (Ig-2), (Ig-3), (Ig-4), (Ih), (Ih-1),(Ih-2), (Ih-3), (Ih-4), (Ij), (Ij-1) or (Ij-2), or any of the compoundsdescribed herein, or a pharmaceutically acceptable salt or a solvate orhydrate thereof.

In some embodiments of methods for suppressing/preventing a MAPK pathwaysignaling provided herein, the BRAF-inhibitor is a compound of formula(I′) or (I) or a compound of any of the subgeneric formulas of formula(I), or a compound as described herein, or a pharmaceutically acceptablesalt or a solvate or hydrate thereof, or a composition comprising acompound of formula (I) or (I′) or a compound of any of the subgenericformulas of formula (I), for example, formulas (Ia), (Ia-1), (Ia-2),(Ib), (Ib-1), (Ib-2), (Ib-1a), (Ib-1b), (Ic), (Ic-1), (Ic-1a), (Ic-2),(Ic-2a), (Id), (Id-1), (Id-1a), (Id-2), (Id-2a), (Ie), (Ie-1), (Ie-1a),(Ie-2), (Ie-2a), (If), (If-1), (If-2), (If-3), (If-4), (Ig), (Ig-1),(Ig-2), (Ig-3), (Ig-4), (Ih), (Ih-1), (Ih-2), (Ih-3), (Ih-4), (Ij),(Ij-1) or (Ij-2), or any of the compounds described herein, or apharmaceutically acceptable salt or a solvate or hydrate thereof.

In another aspect, provided herewith is a method for suppressing theinduction of expression of EGFR ligands in cells. The method includescontacting the mutant BRAF kinase in a cell with a compound of formula(I′) or (I) or a compound of any of the subgeneric formulas of formula(I), or a compound as described herein, or a pharmaceutically acceptablesalt or a solvate or hydrate thereof, or a composition comprising acompound of formula (I) or (I′) or a compound of any of the subgenericformulas of formula (I), for example, formulas (Ia), (Ia-1), (Ia-2),(Ib), (Ib-1), (Ib-2), (Ib-1a), (Ib-1b), (Ic), (Ic-1), (Ic-1a), (Ic-2),(Ic-2a), (Id), (Id-1), (Id-1a), (Id-2), (Id-2a), (Ie), (Ie-1), (Ie-1a),(Ie-2), (Ie-2a), (If), (If-1), (If-2), (If-3), (If-4), (Ig), (Ig-1),(Ig-2), (Ig-3), (Ig-4), (Ih), (Ih-1), (Ih-2), (Ih-3), (Ih-4), (Ij),(Ij-1) or (Ij-2), or any of the compounds described herein, or apharmaceutically acceptable salt or a solvate or hydrate thereof, undercondition sufficient to inhibit the mutant BRAF kinase, wherein theinhibition of BRAF kinase does not induce the expression of EGFRligands. In some embodiments, the method includes administering to asubject an effective amount of a compound of formula (I) to suppress theinduction of expression of EGFR ligands. The variables Y, R³, R⁴, L andZ are as defined in any of the embodiments of formula (I) or subgenericformulas of formula (I) as described herein.

In another aspect, provided herewith is a method for inhibiting a mutantBRAF kinase. The method includes contacting the mutant BRAF kinase in acell with a compound of formula (I′) or (I) or a compound of any of thesubgeneric formulas of formula (I), or a compound as described herein,or a pharmaceutically acceptable salt or a solvate or hydrate thereof,or a composition comprising a compound of formula (I) or (I′) or acompound of any of the subgeneric formulas of formula (I), for example,formulas (Ia), (Ia-1), (Ia-2), (Ib), (Ib-1), (Ib-2), (Ib-1a), (Ib-1b),(Ic), (Ic-1), (Ic-1a), (Ic-2), (Ic-2a), (Id), (Id-1), (Id-1a), (Id-2),(Id-2a), (Ie), (Ie-1), (Ie-1a), (Ie-2), (Ie-2a), (If), (If-1), (If-2),(If-3), (If-4), (Ig), (Ig-1), (Ig-2), (Ig-3), (Ig-4), (Ih), (Ih-1),(Ih-2), (Ih-3), (Ih-4), (Ij), (Ij-1) or (Ij-2), or any of the compoundsdescribed herein, or a pharmaceutically acceptable salt or a solvate orhydrate thereof, under condition sufficient to inhibit the mutant BRAFkinase, wherein the inhibition of BRAF kinase does not cause or inducean activation of a pERK kinase. There is no reactivation of pERK kinaseeven in cells having RAS mutation or upstream receptor tyrosine kinaseactivation. In some embodiments of the methods provided herein, informula (I), Y is —N(R¹)(R²) R¹ and R² are each independently optionallysubstituted alkyl, aryl, heteroaryl, cycloalkyl or R¹ and R² takentogether to form a optionally substituted 5- or 6-memberedheterocycloalkyl ring having from 0-1 heteroatoms selected from O, N orS; R³ is H or C₁₋₆alkyl; R⁴ is halogen or hydrogen; L is a bond, —C(O)—,—C(S)— or —C[═C(R⁵)(R⁶)]—, wherein R⁵ and R⁶ are each independently amember selected from H, R⁷, R^(a), R^(b), R^(c), R^(d), R^(e), R^(f) orR^(g); or R⁵ and R⁶ are taken together to form an optionally substituted5- or 6-membered ring having from 0-4 heteroatoms selected from O, N orS, where N and S are optionally oxidized; and Z is an optionallysubstituted aryl or optionally substituted heteroaryl. In someembodiments, Z is other than an optionally substituted

core, wherein the wavy line indicates point of attachment to the rest ofthe molecule. In some instances, the variables R¹, R², R³, R⁴, L and Zare as defined in any of the embodiments described herein. In someinstances, the BRAF inhibitor interact with the Leucine 505 amino acidresidue in the C-terminal end of an αC helix results in inhibition ofpERK activation. In some instances, the BRAF inhibitor is in directcontact with the Leucine 505 amino acid residue in the C-terminal end ofan αC helix, for example, through the —N(R¹)(R²) moiety.

In another aspect, provided herewith is a method for inhibiting a mutantBRAF kinase in a subject. The method includes administering to thesubject an effective amount of a compound of formula (I′) or (I) or acompound of any of the subgeneric formulas of formula (I), or a compoundas described herein, or a pharmaceutically acceptable salt or a solvateor hydrate thereof, or a composition comprising a compound of formula(I) or (I′) or a compound of any of the subgeneric formulas of formula(I), for example, formulas (Ia), (Ia-1), (Ia-2), (Ib), (Ib-1), (Ib-2),(Ib-1a), (Ib-1b), (Ic), (Ic-1), (Ic-1a), (Ic-2), (Ic-2a), (Id), (Id-1),(Id-1a), (Id-2), (Id-2a), (Ie), (Ie-1), (Ie-1a), (Ie-2), (Ie-2a), (If),(If-1), (If-2), (If-3), (If-4), (Ig), (Ig-1), (Ig-2), (Ig-3), (Ig-4),(Ih), (Ih-1), (Ih-2), (Ih-3), (Ih-4), (Ij), (Ij-1) or (Ij-2), or any ofthe compounds described herein, or a pharmaceutically acceptable salt ora solvate or hydrate thereof. In some embodiments of the methodsprovided herein, in formula (I), Y is —N(R¹)(R²), wherein R¹ and R² areeach independently optionally substituted alkyl, aryl, heteroaryl,cycloalkyl or R¹ and R² taken together to form a optionally substituted5- or 6-membered heterocycloalkyl ring having from 0-1 heteroatomsselected from O, N or S; R³ is H or C₁₋₆alkyl; R⁴ is halogen orhydrogen; L is a bond, —C(O)—, —C(S)— or —C[═C(R⁵)(R⁶)]—, wherein R⁵ andR⁶ are each independently a member selected from H, R⁷, R^(a), R^(b),R^(c), R^(d), R^(e), R^(f) or R^(g); or R⁵ and R⁶ are taken together toform an optionally substituted 5- or 6-membered ring having from 0-4heteroatoms selected from O, N or S, where N and S are optionallyoxidized; and Z is an optionally substituted aryl or optionallysubstituted heteroaryl and wherein the inhibition of BRAF kinase doesnot cause the activation of a pERK kinase. There is no reactivation ofpERK kinase even in cells having RAS mutation or upstream receptortyrosine kinase activation. In some embodiments, Z is other than anoptionally substituted

core, wherein the wavy line indicates point of attachment to the rest ofthe molecule. In some instances, the variables R¹, R², R³, R⁴, L and Zare as defined in any of the embodiments described herein. In someinstances, the BRAF inhibitors interact with the Leucine 505 amino acidresidue in the C-terminal end of an αC helix results in inhibition ofpERK activation. In some instances, the BRAF inhibitor is in directcontact with the Leucine 505 amino acid residue in the C-terminal end ofan αC helix, for example, through the —N(R¹)(R²) or —C(R⁸)(R⁹)(R¹⁰)moiety.

In another aspect, provided herewith is a method for inhibiting theactivity of a mutant BRAF^(V600) protein kinase, for example, in a MPAKpathway. The method includes contacting the BRAF^(V600) mutant with aBRAF inhibitor of formula (I′) or (I) or a compound of any of thesubgeneric formulas of formula (I), or a compound as described herein,or a pharmaceutically acceptable salt or a solvate or hydrate thereof,or a composition comprising a compound of formula (I) or (I′) a compoundof any of the subgeneric formulas of formula (I), for example, formulas(Ia), (Ia-1), (Ia-2), (Ib), (Ib-1), (Ib-2), (Ib-1a), (Ib-1b), (Ic),(Ic-1), (Ic-1a), (Ic-2), (Ic-2a), (Id), (Id-1), (Id-1a), (Id-2),(Id-2a), (Ie), (Ie-1), (Ie-1a), (Ie-2), (Ie-2a), (If), (If-1), (If-2),(If-3), (If-4), (Ig), (Ig-1), (Ig-2), (Ig-3), (Ig-4), (Ih), (Ih-1),(Ih-2), (Ih-3), (Ih-4), (Ij), (Ij-1) or (Ij-2), or any of the compoundsdescribed herein, or a pharmaceutically acceptable salt or a solvate orhydrate thereof, wherein the inhibition of mutant BRAF^(V600) kinasedoes not cause or induce the activation of pERK. In some embodiments,the inhibiting the activity of a mutant BRAF^(V600) protein kinase canbe achieved by regulating the interaction of the —N(R¹)(R²) or—C(R⁸)(R⁹)(R¹⁰) group of the BRAF kinase inhibitor with the Leucine 505amino acid residue in the C-terminal end of an αC helix. For example,the BRAF inhibitor can be in direct contact with the Leucine 505 aminoacid residue in the C-terminal end of an αC helix, for example, via the—N(R¹)(R²) or —C(R⁸)(R⁹)(R¹⁰) group. The cells containing RAF kinase canhave RAS mutation or upstream receptor tyrosine kinase activation. Insome embodiments, the method includes contacting a BRAF^(V600) proteinkinase with a compound of formula (I):

wherein R¹ and R² are each independently optionally substituted alkyl,aryl, heteroaryl, cycloalkyl or R′ and R² taken together to form aoptionally substituted 5- or 6-membered heterocycloalkyl ring havingfrom 0-1 heteroatoms selected from O, N or S; R³ is H or C₁₋₆alkyl; R⁴is halogen or hydrogen; L is a bond, —C(O)—, —C(S)— or —C[═C(R⁵)(R⁶)]—,wherein R⁵ and R⁶ are each independently a member selected from H, R⁷,R^(a), R^(b), R^(c), R^(d), R^(e), R^(f) or R^(g); or R⁵ and R⁶ aretaken together to form an optionally substituted 5- or 6-membered ringhaving from 0-4 heteroatoms selected from O, N or S, where N and S areoptionally oxidized; Z is an optionally substituted aryl or optionallysubstituted heteroaryl. In some embodiments, Z is other than anoptionally substituted

core, wherein the wavy line indicates point of attachment to the rest ofthe molecule. In some instances, the variables R¹, R², R³, R⁴, L and Zare as defined in any of the embodiments described herein.

In another aspect, provided herewith is a method for inhibiting theactivity of a mutant BRAF^(V600) in a subject. The method includesadministering to the subject in need there of an effective amount of aBRAF inhibitor of formula (I′) or (I) or a compound of any of thesubgeneric formulas of formula (I), or a compound as described herein,or a pharmaceutically acceptable salt or a solvate or hydrate thereof,or a composition comprising a compound of formula (I) or (I′) or acompound of any of the subgeneric formulas of formula (I), for example,formulas (Ia), (Ia-1), (Ia-2), (Ib), (Ib-1), (Ib-2), (Ib-1a), (Ib-1b),(Ic), (Ic-1), (Ic-1a), (Ic-2), (Ic-2a), (Id), (Id-1), (Id-1a), (Id-2),(Id-2a), (Ie), (Ie-1), (Ie-1a), (Ie-2), (Ie-2a), (If), (If-1), (If-2),(If-3), (If-4), (Ig), (Ig-1), (Ig-2), (Ig-3), (Ig-4), (Ih), (Ih-1),(Ih-2), (Ih-3), (Ih-4), (Ij), (Ij-1) or (Ij-2), or any of the compoundsdescribed herein, or a pharmaceutically acceptable salt or a solvate orhydrate thereof, wherein the inhibition of mutant BRAF^(V600) kinasedoes not cause or induce the activation of pERK. In some embodiments,the method includes administering to the subject an effective amount ofa compound of formula (I):

wherein R¹ and R² are each independently optionally substituted alkyl,aryl, heteroaryl, cycloalkyl or R′ and R² taken together to form aoptionally substituted 5- or 6-membered heterocycloalkyl ring havingfrom 0-1 heteroatoms selected from O, N or S; R³ is H or C₁₋₆alkyl; R⁴is halogen or hydrogen; L is a bond, —C(O)—, —C(S)— or —C[═C(R⁵)(R⁶)]—,wherein R⁵ and R⁶ are each independently a member selected from H, R⁷,R^(a), R^(b), R^(e), R^(d), R^(e), R^(f) or R^(g); or R⁵ and R⁶ aretaken together to form an optionally substituted 5- or 6-membered ringhaving from 0-4 heteroatoms selected from O, N or S, where N and S areoptionally oxidized; and Z is an optionally substituted aryl oroptionally substituted heteroaryl and wherein the inhibition of BRAFkinase does not cause the activation of a pERK kinase. There is noreactivation of pERK kinase even in cells having RAS mutation orupstream receptor tyrosine kinase activation. In some embodiments, Z isother than an optionally substituted

core, wherein the wavy line indicates point of attachment to the rest ofthe molecule. In some instances, the variables R¹, R², R³, R⁴, L and Zare as defined in any of the embodiments described herein. In someinstances, the BRAF inhibitors interact with the Leucine 505 amino acidresidue in the C-terminal end of an αC helix results in inhibition ofpERK activation. In some instances, the BRAF inhibitor can be in directcontact with the Leucine 505 amino acid residue in the C-terminal end ofan αC helix, for example, through the —N(R¹)(R²) or —C(R⁸)(R⁹)(R¹⁰)moiety.

In another aspect, provided herewith is a method for treating a subjectsuffering from a disease or condition as described herein. In someembodiments, diseases or conditions include a metastatic melanoma, athyroid cancer, a colorectal cancer, a lung cancer or an ovarian cancer.The method includes administering to the subject in need there of aneffective amount of a BRAF inhibitor of formula (I′) or (I) or acompound of any of the subgeneric formulas of formula (I), or a compoundas described herein, or a pharmaceutically acceptable salt or a solvateor hydrate thereof, or a composition comprising a compound of formula(I) or (I′) or a compound of any of the subgeneric formulas of formula(I), for example, formulas (Ia), (Ia-1), (Ia-2), (Ib), (Ib-1), (Ib-2),(Ib-1a), (Ib-1b), (Ic), (Ic-1), (Ic-1a), (Ic-2), (Ic-2a), (Id), (Id-1),(Id-1a), (Id-2), (Id-2a), (Ie), (Ie-1), (Ie-1a), (Ie-2), (Ie-2a), (If),(If-1), (If-2), (If-3), (If-4), (Ig), (Ig-1), (Ig-2), (Ig-3), (Ig-4),(Ih), (Ih-1), (Ih-2), (Ih-3), (Ih-4), (Ij), (Ij-1) or (Ij-2), or any ofthe compounds described herein, or a pharmaceutically acceptable salt ora solvate or hydrate thereof, wherein the inhibition of mutantBRAF^(V600) kinase does not cause or induce the activation of pERK. Insome embodiments, the method includes administering to the subject aneffective amount of a compound of formula (I):

wherein R¹ and R² are each independently optionally substituted alkyl,aryl, heteroaryl, cycloalkyl or R¹ and R² taken together to form aoptionally substituted 5- or 6-membered heterocycloalkyl ring havingfrom 0-1 heteroatoms selected from O, N or S; R³ is H or C₁₋₆alkyl; R⁴is halogen or hydrogen; L is a bond, —C(O)—, —C(S)— or —C[═C(R⁵)(R⁶)]—,wherein R⁵ and R⁶ are each independently a member selected from H, R⁷,R^(a), R^(b), R^(c), R^(d), R^(e), R^(f) or R^(g); or R⁵ and R⁶ aretaken together to form an optionally substituted 5- or 6-membered ringhaving from 0-4 heteroatoms selected from O, N or S, where N and S areoptionally oxidized; and Z is an optionally substituted aryl oroptionally substituted heteroaryl and wherein the inhibition of BRAFkinase does not cause the activation of a pERK kinase. There is noreactivation of pERK kinase even in cells having RAS mutation orupstream receptor tyrosine kinase activation. In some embodiments, Z isother than an optionally substituted

core, wherein the wavy line indicates point of attachment to the rest ofthe molecule. In some instances, the variables R¹, R², R³, R⁴, L and Zare as defined in any of the embodiments described herein. In someinstances, the BRAF inhibitors interact with the Leucine 505 amino acidresidue in the C-terminal end of an αC helix results in inhibition ofpERK activation. In some instances, the BRAF inhibitor can be in directcontact with the Leucine 505 amino acid residue in the C-terminal end ofan αC helix, for example, through the —N(R¹)(R²) or —C(R⁸)(R⁹)(R¹⁰)moiety.

In any of the methods provided herein, the mutant BRAF protein kinasescan have a mutation encoding a V600 amino acid substitution, a L505amino acid substitution or a combination thereof. Exemplary mutant BRAFkinases include BRAF^(V600A), BRAF^(V600M), BRAF^(V600R), BRAF^(V600E),BRAF^(V600K), BRAF^(V600G) or BRAF^(L505H) or combinations thereof. Inone instance, the mutant BRAF kinase has a V600E amino acidsubstitution. In another instance, the mutant BRAF kinase has a V600Kamino acid substitution. In another instance, the mutant BRAF kinase hasa V600 amino acid substitution. In another instance, the mutant BRAFkinase has V600 and L505 substitutions. In another instance, the mutantBRAF kinase has BRAF^(V600E) and BRAF^(L505H) mutations. In anotherinstance, the mutant BRAF kinase has BRAF^(V600K) and BRAF^(L505H)mutations. In another instance, the mutant BRAF kinase has BRAF^(V600A)and BRAF^(L505H) mutations. In another instance, the mutant BRAF kinasehas BRAF^(V600M) and BRAF^(L505H) mutations. In another instance, themutant BRAF kinase has BRAF^(V600R) and BRAF^(L505H) mutations. Inanother instance, the mutant BRAF kinase has BRAF^(V600G) andBRAF^(L505H) mutations.

A compound of formula (I′) or (I) or a compound of any of the subgenericformulas of formula (I), or a compound as described herein, or apharmaceutically acceptable salt or a solvate or hydrate thereof, or acomposition comprising a compound of formula (I) or (I′) or a compoundof any of the subgeneric formulas of formula (I), for example, formulas(Ia), (Ia-1), (Ia-2), (Ib), (Ib-1), (Ib-2), (Ib-1a), (Ib-1b), (Ic),(Ic-1), (Ic-1a), (Ic-2), (Ic-2a), (Id), (Id-1), (Id-1a), (Id-2),(Id-2a), (Ie), (Ie-1), (Ie-1a), (Ie-2), (Ie-2a), (If), (If-1), (If-2),(If-3), (If-4), (Ig), (Ig-1), (Ig-2), (Ig-3), (Ig-4), (Ih), (Ih-1),(Ih-2), (Ih-3), (Ih-4), (Ij), (Ij-1) or (Ij-2), or any of the compoundsdescribed herein, or a pharmaceutically acceptable salt or a solvate orhydrate thereof, can have an IC₅₀ of less than 500 nm, less than 100 nM,less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, orless than 1 nM as determined in a generally accepted RAF kinase activityassay. In some embodiments, a compound as described herein is selectiverelative to other protein kinases, such that the ratio of IC_(ED) foranother kinase assessed comparably, divided by the IC_(ED) for RAFkinase is >20, also >30, also >40, also >50, also >60, also >70,also >80, also >90, also >100, wherein the other protein kinaseincludes, but is not limited to, wild type BRAF and C-raf kinases.

In some embodiments, a compound of formula (I′) or (I) or a compound ofany of the subgeneric formulas of formula (I), or a compound asdescribed herein, or a pharmaceutically acceptable salt or a solvate orhydrate thereof, or a composition comprising a compound of formula (I)or (I′) or a compound of any of the subgeneric formulas of formula (I),for example, formulas (Ia), (Ia-1), (Ia-2), (Ib), (Ib-1), (Ib-2),(Ib-1a), (Ib-1b), (Ic), (Ic-1), (Ic-1a), (Ic-2), (Ic-2a), (Id), (Id-1),(Id-1a), (Id-2), (Id-2a), (Ie), (Ie-1), (Ie-1a), (Ie-2), (Ie-2a), (If),(If-1), (If-2), (If-3), (If-4), (Ig), (Ig-1), (Ig-2), (Ig-3), (Ig-4),(Ih), (Ih-1), (Ih-2), (Ih-3), (Ih-4), (Ij), (Ij-1) or (Ij-2), or any ofthe compounds described herein, or a pharmaceutically acceptable salt ora solvate or hydrate thereof, is a potent inhibitor of mutantBRAF^(V600K/L505H) or BRAF^(V600E/L505H) with an IC₅₀ of less than 1 μM,less than 500 nm, less than 100 nM, less than 50 nM, less than 20 nM,less than 10 nM, less than 5 nM, or less than 1 nM as determined in agenerally accepted RAF kinase activity assay.

Organic Synthetic Techniques

A wide array of organic synthetic techniques exist in the art tofacilitate the construction of potential modulators. Many of theseorganic synthetic methods are described in detail in standard referencesources utilized by those skilled in the art. One example of such areference is March, 1994, Advanced Organic Chemistry; Reactions,Mechanisms and Structure, New York, McGraw Hill. Thus, the techniquesuseful to synthesize a potential modulator of kinase function arereadily available to those skilled in the art of organic chemicalsynthesis.

Alternative Compound Forms or Derivatives

Compounds contemplated herein are described with reference to bothgeneric formulae and specific compounds. In addition, compoundsdisclosed herein may exist in a number of different forms orderivatives, all within the scope of the disclosure. Alternative formsor derivatives, include, for example, (a) prodrugs, and activemetabolites (b) tautomers, isomers (including stereoisomers andregioisomers), and racemic mixtures (c) pharmaceutically acceptablesalts and (d) solid forms, including different crystal forms,polymorphic or amorphous solids, including hydrates and solvatesthereof, and other forms.

(a) Prodrugs and Metabolites

In addition to the present formulae and compounds described herein, thedisclosure also includes prodrugs (generally pharmaceutically acceptableprodrugs), active metabolic derivatives (active metabolites), and theirpharmaceutically acceptable salts.

Prodrugs are compounds or pharmaceutically acceptable salts thereofwhich, when metabolized under physiological conditions or when convertedby solvolysis, yield the desired active compound. Prodrugs include,without limitation, esters, amides, carbamates, carbonates, ureides,solvates, or hydrates of the active compound. Typically, the prodrug isinactive, or less active than the active compound, but may provide oneor more advantageous handling, administration, and/or metabolicproperties. For example, some prodrugs are esters of the activecompound; during metabolysis, the ester group is cleaved to yield theactive drug. Esters include, for example, esters of a carboxylic acidgroup, or S-acyl or O-acyl derivatives of thiol, alcohol, or phenolgroups. In this context, a common example is an alkyl ester of acarboxylic acid. Prodrugs may also include variants wherein an —NH groupof the compound has undergone acylation, such as the 1-position of the1H-pyrrolo[2,3-b]pyridine ring, or the nitrogen of the sulfonamide groupof compounds as described herein, where cleavage of the acyl groupprovides the free —NH group of the active drug. Some prodrugs areactivated enzymatically to yield the active compound, or a compound mayundergo further chemical reaction to yield the active compound. Prodrugsmay proceed from prodrug form to active form in a single step or mayhave one or more intermediate forms which may themselves have activityor may be inactive.

As described in The Practice of Medicinal Chemistry, Ch. 31-32 (Ed.Wermuth, Academic Press, San Diego, Calif., 2001), prodrugs can beconceptually divided into two non-exclusive categories, bioprecursorprodrugs and carrier prodrugs. Generally, bioprecursor prodrugs arecompounds that are inactive or have low activity compared to thecorresponding active drug compound, that contain one or more protectivegroups and are converted to an active form by metabolism or solvolysis.Both the active drug form and any released metabolic products shouldhave acceptably low toxicity. Typically, the formation of active drugcompound involves a metabolic process or reaction that is one of thefollowing types:

Oxidative reactions: Oxidative reactions are exemplified withoutlimitation by reactions such as oxidation of alcohol, carbonyl, and acidfunctionalities, hydroxylation of aliphatic carbons, hydroxylation ofalicyclic carbon atoms, oxidation of aromatic carbon atoms, oxidation ofcarbon-carbon double bonds, oxidation of nitrogen-containing functionalgroups, oxidation of silicon, phosphorus, arsenic, and sulfur, oxidativeN-dealkylation, oxidative O- and S-dealkylation, oxidative deamination,as well as other oxidative reactions.

Reductive reactions: Reductive reactions are exemplified withoutlimitation by reactions such as reduction of carbonyl functionalities,reduction of alcohol functionalities and carbon-carbon double bonds,reduction of nitrogen-containing functional groups, and other reductionreactions.

Reactions without change in the oxidation state: Reactions withoutchange in the state of oxidation are exemplified without limitation byreactions such as hydrolysis of esters and ethers, hydrolytic cleavageof carbon-nitrogen single bonds, hydrolytic cleavage of non-aromaticheterocycles, hydration and dehydration at multiple bonds, new atomiclinkages resulting from dehydration reactions, hydrolyticdehalogenation, removal of hydrogen halide molecule, and other suchreactions.

Carrier prodrugs are drug compounds that contain a transport moiety,e.g., that improves uptake and/or localized delivery to a site(s) ofaction. Desirably for such a carrier prodrug, the linkage between thedrug moiety and the transport moiety is a covalent bond, the prodrug isinactive or less active than the drug compound, the prodrug and anyrelease transport moiety are acceptably non-toxic. For prodrugs wherethe transport moiety is intended to enhance uptake, typically therelease of the transport moiety should be rapid. In other cases, it isdesirable to utilize a moiety that provides slow release, e.g., certainpolymers or other moieties, such as cyclodextrins. (See, e.g., Cheng etal., U.S. Patent Publ. No. 20040077595, incorporated herein byreference.) Such carrier prodrugs are often advantageous for orallyadministered drugs. In some instances, the transport moiety providestargeted delivery of the drug, for example the drug may be conjugated toan antibody or antibody fragment. Carrier prodrugs can, for example, beused to improve one or more of the following properties: increasedlipophilicity, increased duration of pharmacological effects, increasedsite-specificity, decreased toxicity and adverse reactions, and/orimprovement in drug formulation (e.g., stability, water solubility,suppression of an undesirable organoleptic or physiochemical property).For example, lipophilicity can be increased by esterification ofhydroxyl groups with lipophilic carboxylic acids, or of carboxylic acidgroups with alcohols, e.g., aliphatic alcohols. Wermuth, supra.

Metabolites, e.g., active metabolites, overlap with prodrugs asdescribed above, e.g., bioprecursor prodrugs. Thus, such metabolites arepharmacologically active compounds or compounds that further metabolizeto pharmacologically active compounds that are derivatives resultingfrom metabolic processes in the body of a subject. Of these, activemetabolites are such pharmacologically active derivative compounds. Forprodrugs, the prodrug compound is generally inactive or of loweractivity than the metabolic product. For active metabolites, the parentcompound may be either an active compound or may be an inactive prodrug.For example, in some compounds, one or more alkoxy groups can bemetabolized to hydroxyl groups while retaining pharmacologic activityand/or carboxyl groups can be esterified, e.g., glucuronidation. In somecases, there can be more than one metabolite, where an intermediatemetabolite(s) is further metabolized to provide an active metabolite.For example, in some cases a derivative compound resulting frommetabolic glucuronidation may be inactive or of low activity, and can befurther metabolized to provide an active metabolite.

Metabolites of a compound may be identified using routine techniquesknown in the art, and their activities determined using tests such asthose described herein. See, e.g., Bertolini et al., 1997, J. Med.Chem., 40:2011-2016; Shan et al., 1997, J Pharm Sci 86(7):756-757;Bagshawe, 1995, Drug Dev. Res., 34:220-230; Wermuth, supra.

(b) Tautomers, Stereoisomers, and Regioisomers

It is understood that some compounds may exhibit tautomerism. In suchcases, the formulae provided herein expressly depict only one of thepossible tautomeric forms. It is therefore to be understood that theformulae provided herein are intended to represent any tautomeric formof the depicted compounds and are not to be limited merely to thespecific tautomeric form depicted by the drawings of the formulae.

Likewise, some of the compounds disclosed herein may exist asstereoisomers, i.e. having the same atomic connectivity of covalentlybonded atoms yet differing in the spatial orientation of the atoms. Forexample, compounds may be optical stereoisomers, which contain one ormore chiral centers, and therefore, may exist in two or morestereoisomeric forms (e.g. enantiomers or diastereomers). Thus, suchcompounds may be present as single stereoisomers (i.e., essentially freeof other stereoisomers), racemates, and/or mixtures of enantiomersand/or diastereomers. As another example, stereoisomers includegeometric isomers, such as cis- or trans-orientation of substituents onadjacent carbons of a double bond. All such single stereoisomers,racemates and mixtures thereof are intended to be within the scope ofthe disclosure. Unless specified to the contrary, all suchstereoisomeric forms are included within the formulae provided herein.

In some embodiments, a chiral compound disclosed herein is in a formthat contains at least 80% of a single isomer (60% enantiomeric excess(“e.e.”) or diastereomeric excess (“d.e.”)), or at least 85% (70% e.e.or d.e.), 90% (80% e.e. or d.e.), 95% (90% e.e. or d.e.), 97.5% (95%e.e. or d.e.), or 99% (98% e.e. or d.e.). As generally understood bythose skilled in the art, an optically pure compound having one chiralcenter is one that consists essentially of one of the two possibleenantiomers (i.e., is enantiomerically pure), and an optically purecompound having more than one chiral center is one that is bothdiastereomerically pure and enantiomerically pure. In some embodiments,the compound is present in optically pure form, such optically pure formbeing prepared and/or isolated by methods known in the art (e.g. byrecrystallization techniques, chiral synthetic techniques (includingsynthesis from optically pure starting materials), and chromatographicseparation using a chiral column.

(c) Pharmaceutically Acceptable Salts

Unless specified to the contrary, specification of a compound hereinincludes pharmaceutically acceptable salts of such compound. Thus,compounds described herein and recited in any of the claims can be inthe form of pharmaceutically acceptable salts, or can be formulated aspharmaceutically acceptable salts. Contemplated pharmaceuticallyacceptable salt forms include, without limitation, mono, bis, tris,tetrakis, and so on. Pharmaceutically acceptable salts are non-toxic inthe amounts and concentrations at which they are administered. Thepreparation of such salts can facilitate the pharmacological use byaltering the physical characteristics of a compound without preventingit from exerting its physiological effect. Useful alterations inphysical properties include lowering the melting point to facilitatetransmucosal administration and increasing the solubility to facilitateadministering higher concentrations of the drug. A compound describedherein may possess a sufficiently acidic, a sufficiently basic, or bothfunctional groups, and accordingly can react with any of a number ofinorganic or organic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt.

Pharmaceutically acceptable salts include acid addition salts such asthose containing chloride, bromide, iodide, hydrochloride, acetate,phenylacetate, acrylate, ascorbate, aspartate, benzoate,2-phenoxybenzoate, 2-acetoxybenzoate, dinitrobenzoate, hydroxybenzoate,methoxybenzoate, methylbenzoate, bicarbonate, butyne-1,4 dioate,hexyne-1,6-dioate, caproate, caprylate, chlorobenzoate, cinnamate,citrate, decanoate, formate, fumarate, glycolate, gluconate, glucarate,glucuronate, glucose-6-phosphate, glutamate, heptanoate, hexanoate,isethionate, isobutyrate, gamma-hydroxybutyrate, phenylbutyrate,lactate, malate, maleate, hydroxymaleate, methylmaleate, malonate,mandelate, nicotinate, nitrate, isonicotinate, octanoate, oleate,oxalate, pamoate, phosphate, monohydrogenphosphate, dihydrogenphosphate,orthophosphate, metaphosphate, pyrophosphate, 2-phosphoglycerate,3-phosphoglycerate, phthalate, propionate, phenylpropionate, propiolate,pyruvate, quinate, salicylate, 4-aminosalicylate, sebacate, stearate,suberate, succinate, sulfate, pyrosulfate, bisulfate, sulfite,bisulfite, sulfamate, sulfonate, benzenesulfonate (i.e. besylate),ethanesulfonate (i.e. esylate), ethane-1,2-disulfonate,2-hydroxyethanesulfonate (i.e. isethionate), methanesulfonate (i.e.mesylate), naphthalene-1-sulfonate, naphthalene-2-sulfonate (i.e.napsylate), propanesulfonate, p-toluenesulfonate (i.e. tosylate),xylenesulfonates, cyclohexylsulfamate, tartrate, and trifluoroacetate.These pharmaceutically acceptable acid addition salts can be preparedusing the appropriate corresponding acid.

When acidic functional groups, such as carboxylic acid or phenol arepresent, pharmaceutically acceptable salts also include basic additionsalts such as those containing benzathine, chloroprocaine, choline,ethanolamine, diethanolamine, triethanolamine, t-butylamine,dicyclohexylamine, ethylenediamine, N,N′-dibenzylethylenediamine,meglumine, hydroxyethylpyrrolidine, piperidine, morpholine, piperazine,procaine, aluminum, calcium, copper, iron, lithium, magnesium,manganese, potassium, sodium, zinc, ammonium, and mono-, di-, ortri-alkylamines (e.g. diethylamine), or salts derived from amino acidssuch as L-histidine, L-glycine, L-lysine, and L-arginine. For example,see Remington's Pharmaceutical Sciences, 19^(th) ed., Mack PublishingCo., Easton, Pa., Vol. 2, p. 1457, 1995. These pharmaceuticallyacceptable base addition salts can be prepared using the appropriatecorresponding base.

Pharmaceutically acceptable salts can be prepared by standardtechniques. For example, the free-base form of a compound can bedissolved in a suitable solvent, such as an aqueous or aqueous-alcoholsolution containing the appropriate acid and then isolated byevaporating the solution. In another example, a salt can be prepared byreacting the free base and acid in an organic solvent. If the particularcompound is an acid, the desired pharmaceutically acceptable salt may beprepared by any suitable method, for example, treatment of the free acidwith an appropriate inorganic or organic base.

(d) Other Compound Forms

In the case of agents that are solids, it is understood by those skilledin the art that the compounds and salts may exist in different crystalor polymorphic forms, or may be formulated as co-crystals, or may be inan amorphous form, or may be any combination thereof (e.g. partiallycrystalline, partially amorphous, or mixtures of polymorphs) all ofwhich are intended to be within the scope of the disclosure andspecified formulae. Whereas salts are formed by acid/base addition, i.e.a free base or free acid of the compound of interest forms an acid/basereaction with a corresponding addition base or addition acid,respectively, resulting in an ionic charge interaction, co-crystals area new chemical species that is formed between neutral compounds,resulting in the compound and an additional molecular species in thesame crystal structure.

In some instances, compounds described herein are complexed with an acidor a base, including base addition salts such as ammonium, diethylamine,ethanolamine, ethylenediamine, diethanolamine, t-butylamine, piperazine,meglumine; acid addition salts, such as acetate, acetylsalicylate,besylate, camsylate, citrate, formate, fumarate, glutarate,hydrochlorate, maleate, mesylate, nitrate, oxalate, phosphate,succinate, sulfate, tartrate, thiocyanate and tosylate; and amino acidssuch as alanine, arginine, asparagine, aspartic acid, cysteine,glutamine, glutamic acid, glycine, histidine, isoleucine, leucine,lysine, methionine, phenylalanine, proline, serine, threonine,tryptophan, tyrosine or valine. In combining the compound disclosedherein with the acid or base, an amorphous complex is preferably formedrather than a crystalline material such as a typical salt or co-crystal.In some instances, the amorphous form of the complex is facilitated byadditional processing, such as by spray-drying, mechanochemical methodssuch as roller compaction, or microwave irradiation of the parentcompound mixed with the acid or base. Such methods may also includeaddition of ionic and/or non-ionic polymer systems, including, but notlimited to, hydroxypropyl methyl cellulose acetate succinate (HPMCAS)and methacrylic acid copolymer (e.g. Eudragit® L100-55), that furtherstabilize the amorphous nature of the complex. Such amorphous complexesprovide several advantages. For example, lowering of the meltingtemperature relative to the free base facilitates additional processing,such as hot melt extrusion, to further improve the biopharmaceuticalproperties of the compound. Also, the amorphous complex is readilyfriable, which provides improved compression for loading of the solidinto capsule or tablet form.

Additionally, the formulae are intended to cover hydrated or solvated aswell as unhydrated or unsolvated forms of the identified structures. Forexample, the indicated compounds include both hydrated and non-hydratedforms. Other examples of solvates include the structures in combinationwith a suitable solvent, such as isopropanol, ethanol, methanol,dimethyl sulfoxide, ethyl acetate, acetic acid, or ethanolamine.

IV. Formulations and Administration

In another aspect, some embodiments provide for pharmaceuticalcompositions comprising/including a pharmaceutically acceptable carrieror excipient and a compound described herein or a pharmaceuticallyacceptable salt or solvate thereof. An exemplary embodiment provides apharmaceutical formulation comprising/including a compound as describedherein. In one embodiment, the compound has any of formulas I, and Ia toIn.

The methods and compounds will typically be used in therapy for humansubjects. However, they may also be used to treat similar or identicalindications in other animal subjects. Compounds described herein can beadministered by different routes, including injection (i.e. parenteral,including intravenous, intraperitoneal, subcutaneous, andintramuscular), oral, transdermal, transmucosal, rectal, or inhalant.Such dosage forms should allow the compound to reach target cells. Otherfactors are well known in the art, and include considerations such astoxicity and dosage forms that retard the compound or composition fromexerting its effects. Techniques and formulations generally may be foundin Remington: The Science and Practice of Pharmacy, 21^(st) edition,Lippincott, Williams and Wilkins, Philadelphia, Pa., 2005 (herebyincorporated by reference herein).

In some embodiments, compositions will comprise pharmaceuticallyacceptable carriers or excipients, such as fillers, binders,disintegrants, glidants, lubricants, complexing agents, solubilizers,and surfactants, which may be chosen to facilitate administration of thecompound by a particular route. Examples of carriers include calciumcarbonate, calcium phosphate, various sugars such as lactose, glucose,or sucrose, types of starch, cellulose derivatives, gelatin, lipids,liposomes, nanoparticles, and the like. Carriers also includephysiologically compatible liquids as solvents or for suspensions,including, for example, sterile solutions of water for injection (WFI),saline solution, dextrose solution, Hank's solution, Ringer's solution,vegetable oils, mineral oils, animal oils, polyethylene glycols, liquidparaffin, and the like. Excipients may also include, for example,colloidal silicon dioxide, silica gel, talc, magnesium silicate, calciumsilicate, sodium aluminosilicate, magnesium trisilicate, powderedcellulose, macrocrystalline cellulose, carboxymethyl cellulose,cross-linked sodium carboxymethylcellulose, sodium benzoate, calciumcarbonate, magnesium carbonate, stearic acid, aluminum stearate, calciumstearate, magnesium stearate, zinc stearate, sodium stearyl fumarate,syloid, stearowet C, magnesium oxide, starch, sodium starch glycolate,glyceryl monostearate, glyceryl dibehenate, glyceryl palmitostearate,hydrogenated vegetable oil, hydrogenated cotton seed oil, castor seedoil mineral oil, polyethylene glycol (e.g. PEG 4000-8000),polyoxyethylene glycol, poloxamers, povidone, crospovidone,croscarmellose sodium, alginic acid, casein, methacrylic aciddivinylbenzene copolymer, sodium docusate, cyclodextrins (e.g.2-hydroxypropyl-.delta.-cyclodextrin), polysorbates (e.g. polysorbate80), cetrimide, TPGS (d-alpha-tocopheryl polyethylene glycol 1000succinate), magnesium lauryl sulfate, sodium lauryl sulfate,polyethylene glycol ethers, di-fatty acid ester of polyethylene glycols,or a polyoxyalkylene sorbitan fatty acid ester (e.g., polyoxyethylenesorbitan ester Tween®), polyoxyethylene sorbitan fatty acid esters,sorbitan fatty acid ester, e.g. a sorbitan fatty acid ester from a fattyacid such as oleic, stearic or palmitic acid, mannitol, xylitol,sorbitol, maltose, lactose, lactose monohydrate or lactose spray dried,sucrose, fructose, calcium phosphate, dibasic calcium phosphate,tribasic calcium phosphate, calcium sulfate, dextrates, dextran,dextrin, dextrose, cellulose acetate, maltodextrin, simethicone,polydextrosem, chitosan, gelatin, HPMC (hydroxypropyl methylcelluloses), HPC (hydroxypropyl cellulose), hydroxyethyl cellulose, andthe like.

Pharmaceutical formulations may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Such a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to700 mg, more preferably 5 mg to 100 mg of a compound described herein(as a free-base, solvate (including hydrate) or salt, in any form),depending on the condition being treated, the route of administration,and the age, weight and condition of the patient. Preferred unit dosageformulations are those containing a daily dose, weekly dose, monthlydose, a sub-dose or an appropriate fraction thereof, of an activeingredient. Furthermore, such pharmaceutical formulations may beprepared by any of the methods well known in the pharmacy art.

Pharmaceutical formulations may be adapted for administration by anyappropriate route, for example by the oral (including capsules, tablets,liquid-filled capsules, disintegrating tablets, immediate, delayed andcontrolled release tablets, oral strips, solutions, syrups, buccal andsublingual), rectal, nasal, inhalation, topical (including transdermal),vaginal or parenteral (including subcutaneous, intramuscular,intravenous or intradermal) route. Such formulations may be prepared byany method known in the art of pharmacy, for example by bringing intoassociation the active ingredient with the carrier(s), excipient(s) ordiluent. Generally, the carrier, excipient or diluent employed in thepharmaceutical formulation is “non-toxic,” meaning that it/they is/aredeemed safe for consumption in the amount delivered in thepharmaceutical composition, and “inert” meaning that it/they does/do notappreciably react with or result in an undesired effect on thetherapeutic activity of the active ingredient.

In some embodiments, oral administration may be used. Pharmaceuticalpreparations for oral use can be formulated into conventional oraldosage forms such as discreet units capsules, tablets, and liquidpreparations such as syrups, elixirs, and concentrated drops. Compoundsdescribed herein may be combined with solid excipients, optionallygrinding a resulting mixture, and processing the mixture of granules,after adding suitable auxiliaries, if desired, to obtain, for example,tablets, coated tablets, hard capsules, soft capsules, solutions (e.g.aqueous, alcoholic, or oily solutions) and the like. Suitable excipientsare, in particular, fillers such as sugars, including lactose, glucose,sucrose, mannitol, or sorbitol; cellulose preparations, for example,corn starch, wheat starch, rice starch, potato starch, gelatin, gumtragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodiumcarboxymethylcellulose (CMC), and/or polyvinylpyrrolidone (PVP:povidone); oily excipients, including vegetable and animal oils, such assunflower oil, olive oil, or cod-liver oil. The oral dosage formulationsmay also contain disintegrating agents, such as the cross-linkedpolyvinylpyrrolidone, agar, or alginic acid, or a salt thereof such assodium alginate; a lubricant, such as talc or magnesium stearate; aplasticizer, such as glycerol or sorbitol; a sweetening such as sucrose,fructose, lactose, or aspartame; a natural or artificial flavoringagent, such as peppermint, oil of wintergreen, or cherry flavoring; ordye-stuffs or pigments, which may be used for identification orcharacterization of different doses or combinations, such as unitdosages. Also provided are dragee cores with suitable coatings. For thispurpose, concentrated sugar solutions may be used, which may optionallycontain, for example, gum arabic, talc, poly-vinylpyrrolidone, carbopolgel, polyethylene glycol, and/or titanium dioxide, lacquer solutions,and suitable organic solvents or solvent mixtures. Oral fluids such assolutions, syrups and elixirs can be prepared in dosage unit form sothat a given quantity contains a predetermined amount of the compound.

Pharmaceutical preparations that can be used orally include push-fitcapsules made of gelatin (“gelcaps”), as well as soft, sealed capsulesmade of gelatin, and a plasticizer, such as glycerol or sorbitol. Thepush-fit capsules can contain the active ingredients in admixture withfiller such as lactose, binders such as starches, and/or lubricants suchas talc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols.

In some embodiments, injection (parenteral administration) may be used,e.g., intramuscular, intravenous, intraperitoneal, and/or subcutaneous.Compounds described herein for injection may be formulated in sterileliquid solutions, preferably in physiologically compatible buffers orsolutions, such as saline solution, Hank's solution, or Ringer'ssolution. Dispersions may also be prepared in non-aqueous solutions,such as glycerol, propylene glycol, ethanol, liquid polyethyleneglycols, triacetin, and vegetable oils. Solutions may also contain apreservative, such as methylparaben, propylparaben, chlorobutanol,phenol, sorbic acid, thimerosal, and the like. In addition, thecompounds may be formulated in solid form, including, for example,lyophilized forms, and redissolved or suspended prior to use. Theformulations may be presented in unit-dose or multi-dose containers, forexample sealed ampoules and vials, and may be stored in a freeze-dried(lyophilized) condition requiring only the addition of the sterileliquid carrier, for example water for injection, immediately prior touse.

In some embodiments, transmucosal, topical or transdermal administrationmay be used. In such formulations of compounds described herein,penetrants appropriate to the barrier to be permeated are used. Suchpenetrants are generally known in the art, and include, for example, fortransmucosal administration, bile salts and fusidic acid derivatives. Inaddition, detergents may be used to facilitate permeation. Transmucosaladministration, for example, may be through nasal sprays orsuppositories (rectal or vaginal). Compositions of compounds describedherein for topical administration may be formulated as oils, creams,lotions, ointments, and the like by choice of appropriate carriers knownin the art. Suitable carriers include vegetable or mineral oils, whitepetrolatum (white soft paraffin), branched chain fats or oils, animalfats and high molecular weight alcohol (greater than C₁₂). In someembodiments, carriers are selected such that the active ingredient issoluble. Emulsifiers, stabilizers, humectants and antioxidants may alsobe included as well as agents imparting color or fragrance, if desired.Creams for topical application are preferably formulated from a mixtureof mineral oil, self-emulsifying beeswax and water in which mixture theactive ingredient, dissolved in a small amount of solvent (e.g., anoil), is admixed. Additionally, administration by transdermal means maycomprise a transdermal patch or dressing such as a bandage impregnatedwith an active ingredient and optionally one or more carriers ordiluents known in the art. To be administered in the form of atransdermal delivery system, the dosage administration will becontinuous rather than intermittent throughout the dosage regimen.

In some embodiments, compounds are administered as inhalants. Compoundsdescribed herein may be formulated as dry powder or a suitable solution,suspension, or aerosol. Powders and solutions may be formulated withsuitable additives known in the art. For example, powders may include asuitable powder base such as lactose or starch, and solutions maycomprise propylene glycol, sterile water, ethanol, sodium chloride andother additives, such as acid, alkali and buffer salts. Such solutionsor suspensions may be administered by inhaling via spray, pump,atomizer, or nebulizer, and the like. The compounds described herein mayalso be used in combination with other inhaled therapies, for examplecorticosteroids such as fluticasone proprionate, beclomethasonedipropionate, triamcinolone acetonide, budesonide, and mometasonefuroate; beta agonists such as albuterol, salmeterol, and formoterol;anticholinergic agents such as ipratroprium bromide or tiotropium;vasodilators such as treprostinal and iloprost; enzymes such as DNAase;therapeutic proteins; immunoglobulin antibodies; an oligonucleotide,such as single or double stranded DNA or RNA, siRNA; antibiotics such astobramycin; muscarinic receptor antagonists; leukotriene antagonists;cytokine antagonists; protease inhibitors; cromolyn sodium; nedocrilsodium; and sodium cromoglycate.

The amounts of various compounds to be administered can be determined bystandard procedures taking into account factors such as the compoundactivity (in vitro, e.g. the compound IC₅₀ vs. target, or in vivoactivity in animal efficacy models), pharmacokinetic results in animalmodels (e.g. biological half-life or bioavailability), the age, size,and weight of the subject, and the disorder associated with the subject.The importance of these and other factors are well known to those ofordinary skill in the art. Generally, a dose will be in the range ofabout 0.01 to 50 mg/kg, also about 0.1 to 20 mg/kg of the subject beingtreated. Multiple doses may be used.

The compounds described herein may also be used in combination withother therapies for treating the same disease. Such combination useincludes administration of the compounds and one or more othertherapeutics at different times, or co-administration of the compoundand one or more other therapies. In some embodiments, dosage may bemodified for one or more of the compounds described herein or othertherapeutics used in combination, e.g., reduction in the amount dosedrelative to a compound or therapy used alone, by methods well known tothose of ordinary skill in the art.

It is understood that use in combination includes use with othertherapies, drugs, medical procedures etc., where the other therapy orprocedure may be administered at different times (e.g. within a shorttime, such as within hours (e.g. 1, 2, 3, 4-24 hours), or within alonger time (e.g. 1-2 days, 2-4 days, 4-7 days, 1-4 weeks)) than acompound described herein, or at the same time as a compound describedherein. Use in combination also includes use with a therapy or medicalprocedure that is administered once or infrequently, such as surgery,along with a compound described herein administered within a short timeor longer time before or after the other therapy or procedure. In someembodiments, the disclosure provides for delivery of a compounddescribed herein and one or more other drug therapeutics delivered by adifferent route of administration or by the same route ofadministration. The use in combination for any route of administrationincludes delivery of a compound described herein and one or more otherdrug therapeutics delivered by the same route of administration togetherin any formulation, including formulations where the two compounds arechemically linked in such a way that they maintain their therapeuticactivity when administered. In one aspect, the other drug therapy may beco-administered with a compound described herein. Use in combination byco-administration includes administration of co-formulations orformulations of chemically joined compounds, or administration of two ormore compounds in separate formulations within a short time of eachother (e.g. within an hour, 2 hours, 3 hours, up to 24 hours),administered by the same or different routes. Co-administration ofseparate formulations includes co-administration by delivery via onedevice, for example the same inhalant device, the same syringe, etc., oradministration from separate devices within a short time of each other.Co-formulations of a compound described herein and one or moreadditional drug therapies delivered by the same route includespreparation of the materials together such that they can be administeredby one device, including the separate compounds combined in oneformulation, or compounds that are modified such that they arechemically joined, yet still maintain their biological activity. Suchchemically joined compounds may have a linkage that is substantiallymaintained in vivo, or the linkage may break down in vivo, separatingthe two active components.

V. Kinase Targets and Indications

Protein kinases play key roles in propagating biochemical signals indiverse biological pathways. More than 500 kinases have been described,and specific kinases have been implicated in a wide range of diseases orconditions (i.e., indications), including for example withoutlimitation, cancer, cardiovascular disease, inflammatory disease,neurological disease, and other diseases. As such, kinases representimportant control points for small molecule therapeutic intervention.Specific target protein kinases contemplated by the disclosure aredescribed in the art, including, without limitation, protein kinases asdescribed in U.S. patent application Ser. No. 11/473,347 (see also, PCTpublication WO2007002433), the disclosure of which is herebyincorporated by reference as it relates to such kinase targets, as wellas the following:

A-Raf:

Target kinase A-Raf (i.e., v-raf murine sarcoma 3611 viral oncogenehomolog 1) is a 67.6 kDa serine/threonine kinase encoded by chromosomeXp11.4-p11.2 (symbol: ARAF). The mature protein comprises RBD (i.e., Rasbinding domain) and phorbol-ester/DAG-type zinc finger domain and isinvolved in the transduction of mitogenic signals from the cell membraneto the nucleus. A-Raf inhibitors may be useful in treating neurologicdiseases such as multi-infarct dementia, head injury, spinal cordinjury, Alzheimer's disease (AD), Parkinson's disease; neoplasticdiseases including, but not limited to, melanoma, glioma, sarcoma,carcinoma (e.g. colorectal, lung, breast, pancreatic, thyroid, renal,ovarian), lymphoma (e.g. histiocytic lymphoma), neurofibromatosis,myelodysplastic syndrome, leukemia, tumor angiogenesis; pain ofneuropathic or inflammatory origin, including acute pain, chronic pain,cancer-related pain and migraine; and diseases associated with muscleregeneration or degeneration, including, but not limited to, vascularrestenosis, sarcopenia, muscular dystrophies (including, but not limitedto, Duchenne, Becker, Emery-Dreifuss, Limb-Girdle, Facioscapulohumeral,Myotonic, Oculopharyngeal, Distal and Congenital Muscular Dystrophies),motor neuron diseases (including, but not limited to, amyotrophiclateral sclerosis, infantile progressive spinal muscular atrophy,intermediate spinal muscular atrophy, juvenile spinal muscular atrophy,spinal bulbar muscular atrophy, and adult spinal muscular atrophy),inflammatory myopathies (including, but not limited to, dermatomyositis,polymyositis, and inclusion body myositis), diseases of theneuromuscular junction (including, but not limited to, myastheniagravis, Lambert-Eaton syndrome, and congenital myasthenic syndrome),myopathies due to endocrine abnormalities (including, but not limitedto, hyperthyroid myopathy and hypothyroid myopathy) diseases ofperipheral nerve (including, but not limited to, Charcot-Marie-Toothdisease, Dejerine-Sottas disease, and Friedreich's ataxia), othermyopathies (including, but not limited to, myotonia congenita,paramyotonia congenita, central core disease, nemaline myopathy,myotubular myopathy, and periodic paralysis), and metabolic diseases ofmuscle (including, but not limited to, phosphorylase deficiency, acidmaltase deficiency, phosphofructokinase deficiency, debrancher enzymedeficiency, mitochondrial myopathy, carnitine deficiency, carnitinepalmatyl transferase deficiency, phosphoglycerate kinase deficiency,phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency,and myoadenylate deaminase deficiency).

BRAF:

Target kinase BRAF (i.e., v-raf murine sarcoma viral oncogene homologB1) is a 84.4 kDa serine/threonine kinase encoded by chromosome 7q34(symbol: BRAF). The mature protein comprises RBD (i.e., Ras bindingdomain), Cl (i.e., protein kinase C conserved region 1) and STK (i.e.,serine/threonine kinase) domains.

Target kinase BRAF is involved in the transduction of mitogenic signalsfrom the cell membrane to the nucleus and may play a role in thepostsynaptic responses of hippocampal neurons. As such, genes of the RAFfamily encode kinases that are regulated by Ras and mediate cellularresponses to growth signals. Indeed, BRAF kinase is a key component ofthe RAS→Raf→MEK→ERK/MAP kinase signaling pathway, which plays afundamental role in the regulation of cell growth, division andproliferation, and, when constitutively activated, causes tumorigenesis.Among several isoforms of Raf kinase, the B-type, or BRAF, is thestrongest activator of the downstream MAP kinase signaling.

The BRAF gene is frequently mutated in a variety of human tumors,especially in malignant melanoma and colon carcinoma. The most commonreported mutation was a missense thymine (T) to adenine (A) transversionat nucleotide 1796 (T1796A; amino acid change in the BRAF protein isVal<600> to Glu<600>) observed in 80% of malignant melanoma tumors.Functional analysis reveals that this transversion is the only detectedmutation that causes constitutive activation of BRAF kinase activity,independent of RAS activation, by converting BRAF into a dominanttransforming protein. Based on precedents, human tumors developresistance to kinase inhibitors by mutating a specific amino acid in thecatalytic domain as the “gatekeeper”. (Balak, et. al., Clin Cancer Res.2006, 12:6494-501). Mutation of Thr-529 in BRAF to Ile is thusanticipated as a mechanism of resistance to BRAF inhibitors, and thiscan be envisioned as a transition in codon 529 from ACC to ATC.

Niihori et al., report that in 43 individuals withcardio-facio-cutaneous (CFC) syndrome, they identified two heterozygousKRAS mutations in three individuals and eight BRAF mutations in 16individuals, suggesting that dysregulation of the RAS-RAF-ERK pathway isa common molecular basis for the three related disorders (Niihori etal., Nat Genet. 2006, 38(3):294-6).

Many cancers associated with dysregulation of the RAS-RAF-ERK pathway,such as cancers having BRAF V600, such as V600E mutations or NRASmutations, may be treated with Raf kinase inhibitors, such as the PanRaf kinase inhibitors as described herein. The ability of thesecompounds to inhibit multiple Raf kinase targets, including c-Raf-1,BRAF, and BRAF V600, such as V600E, provides additional benefits forinhibiting activating mutations in this pathway, with such cancers lesslikely to develop resistance to such inhibitors as they are targetingseveral points in the pathway. Pan Raf kinase inhibitors as describedherein may be useful in treating a variety of cancers, including, butnot limited to, melanoma, glioma, glioblastoma mulitforme, pilocyticastrocytoma, carcinoma (e.g. gastrointestinal, liver, biliary tract,bile duct (cholangiocarcinoma), colorectal, lung, brain, bladder,gallbladder, breast, pancreatic, thyroid, kidney, ovarian,adrenocortical, prostate), gastrointestinal stromal tumors, medullarythyroid cancer, tumor angiogenesis, acute myeloid leukemia, chronicmyelomonocytic leukemia, childhood acute lymphoblastic leukemia, plasmacell leukemia, and multiple myeloma. See McDermott et al., PNAS, 2007,104(50): 19936-19941; and Jaiswal et al., PLoS One, 2009, 4(5):e5717.

c-Raf-1:

Target kinase c-Raf-1 (i.e., v-raf murine sarcoma viral oncogenehomolog 1) is a 73.0 kDa STK encoded by chromosome 3p25 (symbol: RAF1).c-Raf-1 can be targeted to the mitochondria by BCL2 (i.e., oncogeneB-cell leukemia 2) which is a regulator of apoptotic cell death. Activec-Raf-1 improves BCL2-mediated resistance to apoptosis, and c-Raf-1phosphorylates BAD (i.e., BCL2-binding protein). c-Raf-1 is implicatedin carcinomas, including colorectal, ovarian, lung and renal cellcarcinoma. c-Raf-1 is also implicated as an important mediator of tumorangiogenesis (Hood, J. D. et al., 2002, Science 296, 2404). c-Raf-1inhibitors may also be useful for the treatment of acute myeloidleukemia and myelodysplastic syndromes (Crump, Curr Pharm Des 2002,8(25):2243-8). c-Raf-1 activators may be useful as treatment forneuroendocrine tumors, such as medullary thyroid cancer, carcinoid,small cell lung cancer and pheochromocytoma (Kunnimalaiyaan et al.,Anticancer Drugs 2006, 17(2): 139-42).

Raf inhibitors (A-Raf and/or BRAF and/or c-Raf-1) may be useful intreating A-Raf-mediated, BRAF-mediated or c-Raf-1-mediated diseases orconditions selected from the group consisting of neurologic diseases,including, but not limited to, multi-infarct dementia, head injury,spinal cord injury, Alzheimer's disease (AD), Parkinson's disease,seizures and epilepsy; neoplastic diseases including, but not limitedto, melanoma, glioma, glioblastoma multiforme, pilocytic astrocytoma,sarcoma, carcinoma (e.g. gastrointestinal, liver, biliary tract, bileduct (cholangiocarcinoma), colorectal, lung, brain, bladder,gallbladder, breast, pancreatic, thyroid, renal, ovarian,adrenocortical, prostate), lymphoma (e.g. histiocytic lymphoma)neurofibromatosis, acute myeloid leukemia, myelodysplastic syndrome,leukemia, chronic myelomonocytic leukemia, childhood, acutelymphoblastic leukemia, plasma cell leukemia, multiple myeloma, tumorangiogenesis, gastrointestinal stromal tumors, neuroendocrine tumorssuch as medullary thyroid cancer, carcinoid, small cell lung cancer,Kaposi's sarcoma, and pheochromocytoma; pain of neuropathic orinflammatory origin, including, but not limited to, acute pain, chronicpain, cancer-related pain, and migraine; cardiovascular diseasesincluding, but not limited to, heart failure, ischemic stroke, cardiachypertrophy, thrombosis (e.g. thrombotic microangiopathy syndromes),atherosclerosis, and reperfusion injury; inflammation and/orproliferation including, but not limited to, psoriasis, eczema,arthritis and autoimmune diseases and conditions, osteoarthritis,endometriosis, scarring, vascular restenosis, fibrotic disorders,rheumatoid arthritis, inflammatory bowel disease (IBD); immunodeficiencydiseases, including, but not limited to, organ transplant rejection,graft versus host disease, and Kaposi's sarcoma associated with HIV;renal, cystic, or prostatic diseases, including, but not limited to,diabetic nephropathy, polycystic kidney disease, nephrosclerosis,glomerulonephritis, prostate hyperplasia, polycystic liver disease,tuberous sclerosis, Von Hippel Lindau disease, medullary cystic kidneydisease, nephronophthisis, and cystic fibrosis; metabolic disorders,including, but not limited to, obesity; infection, including, but notlimited to Helicobacter pylori, Hepatitis and Influenza viruses, fever,HIV, and sepsis; pulmonary diseases including, but not limited to,chronic obstructive pulmonary disease (COPD) and acute respiratorydistress syndrome (ARDS); genetic developmental diseases, including, butnot limited to, Noonan's syndrome, Costello syndrome,(faciocutaneoskeletal syndrome), LEOPARD syndrome, cardio-faciocutaneoussyndrome (CFC), and neural crest syndrome abnormalities causingcardiovascular, skeletal, intestinal, skin, hair and endocrine diseases;and diseases associated with muscle regeneration or degeneration,including, but not limited to, sarcopenia, muscular dystrophies(including, but not limited to, Duchenne, Becker, Emery-Dreifuss,Limb-Girdle, Facioscapulohumeral, Myotonic, Oculopharyngeal, Distal andCongenital Muscular Dystrophies), motor neuron diseases (including, butnot limited to, amyotrophic lateral sclerosis, infantile progressivespinal muscular atrophy, intermediate spinal muscular atrophy, juvenilespinal muscular atrophy, spinal bulbar muscular atrophy, and adultspinal muscular atrophy), inflammatory myopathies (including, but notlimited to, dermatomyositis, polymyositis, and inclusion body myositis),diseases of the neuromuscular junction (including, but not limited to,myasthenia gravis, Lambert-Eaton syndrome, and congenital myasthenicsyndrome), myopathies due to endocrine abnormalities (including, but notlimited to, hyperthyroid myopathy and hypothyroid myopathy) diseases ofperipheral nerve (including, but not limited to, Charcot-Marie-Toothdisease, Dejerine-Sottas disease, and Friedreich's ataxia), othermyopathies (including, but not limited to, myotonia congenita,paramyotonia congenita, central core disease, nemaline myopathy,myotubular myopathy, and periodic paralysis), and metabolic diseases ofmuscle (including, but not limited to, phosphorylase deficiency, acidmaltase deficiency, phosphofructokinase deficiency, debrancher enzymedeficiency, mitochondrial myopathy, carnitine deficiency, carnitinepalmatyl transferase deficiency, phosphoglycerate kinase deficiency,phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency,and myoadenylate deaminase deficiency).

Erk2:

Target kinase Erk2 (i.e., extracellular signal-regulated kinase 2) is a41.4 kDa dual function serine/threonine-tyrosine kinase encoded bychromosome 22q11.2 (symbol: MAPK1). Erk2 is a member of themitogen-activated protein (MAP) kinase family and is alternatively knownas mitogen-activated protein kinase 1 (i.e., MAPK1). MAP kinases act asan integration point for multiple biochemical signals, and are involvedin a wide variety of cellular processes such as proliferation,differentiation, transcription regulation and development.

The activation of Erk2 requires phosphorylation by upstream kinases.Upon activation, Erk2 translocates to the nucleus of the stimulatedcells, where it phosphorylates nuclear targets, in addition to othertargets including microtubule associated protein 2, myelin basic proteinand ELK1. MacKenzie et al. state that the cAMP-specificphosphodiesterase family 4, subfamily D, isoform 3 (i.e., PDE4D3) isshown to have FQF (i.e., Phe-Gln-Phe) and KIM (i.e., Kinase InteractionMotif) docking sites for Erk2. These sites straddle the Ser(579) targetresidue for Erk2 phosphorylation of PDE4D3. Mutation of either or bothof these docking sites prevent Erk2 from being co-immunoprecipitatedwith PDE4D3, ablate the ability of epidermal growth factor (EGF) toinhibit PDE4D3 through Erk2 action in transfected COS cells, andattenuate the ability of Erk2 to phosphorylate PDE4D3 in vitro. The twoconserved NH(2)-terminal blocks of sequence, called upstream conservedregions 1 and 2 (i.e., UCR1 and UCR2), that characterize PDE4 longisoforms, are proposed to amplify the small, inherent inhibitory effectthat Erk2 phosphorylation exerts on the PDE4D catalytic unit. Incontrast to this, the lone intact UCR2 region found in PDE4D1 directsCOOH-terminal Erk2 phosphorylation to cause the activation of this shortisoform. From the analysis of PDE4D3 truncates, it is suggested thatUCR1 and UCR2 provide a regulatory signal integration module that servesto orchestrate the functional consequences of Erk2 phosphorylation. ThePDE4D gene thus encodes a series of isoenzymes that are either inhibitedor activated by Erk2 phosphorylation and thereby offers the potentialfor ERK2 activation either to increase or decrease cAMP levels incellular compartments (MacKenzie et al., J Biol Chem 2000,275(22):16609-17).

According to OMIM, Pleschka et al. (Nature Cell Biol., 2001, 3: 301-305)proposed that Erk2 regulates a cellular factor involved in the viralnuclear export protein function. They suggested that local applicationof MEK inhibitors may have only minor toxic effects on the host whileinhibiting viral replication without giving rise to drug-resistant virusvariants (OMIM MIM Number: 176948: Oct. 27, 2005). Erk2 is involved incytokine signaling and is a target for treating inflammation. Ramesh andPhilipp state that lipoproteins are the key inflammatory molecule typeof Borrelia burgdorferi, the spirochete that causes Lyme disease. Theyinvestigated whether specific inhibition of p38 and Erk1/2 MAPK wouldinhibit TNF-alpha and IL-6 production and thus astrocyte apoptosis, andproliferation, respectively. Lipoprotein-stimulated IL-6 production wasunaffected by the MAPK inhibitors. In contrast, inhibition of both p38and Erk1/2 significantly diminished TNF-alpha production, and totallyabrogated production of this cytokine when both MAPK pathways wereinhibited simultaneously. MAPK inhibition thus may be considered as astrategy to control inflammation and apoptosis in Lyme neuroborreliosis(Ramesh and Philipp, Neurosci Lett 2005, 384(1-2):112-6). The role ofErk2 in signaling of cell differentiation, proliferation and survivalsuggests that inhibition of Erk2 may be therapeutic for several types ofcancer. Husain et al. studied the effect of NSAIDs on MAPK activity andphosphorylation in gastric cancer. They conclude that NS-398 (aselective COX-2 inhibitor) and indomethacin (a non-selective NSAID)significantly inhibit proliferation and growth of human gastric cancercell line MKN28. This effect is mediated by NSAID-induced inhibition ofMAPK (ERK2) kinase signaling pathway, essential for cell proliferation(Husain et al., Life Sci 2001, 69(25-6):3045-54). Erk2 inhibitors may beuseful in treating cancer, including gastric cancer, and in treatinginflammation, including control of inflammation and apoptosis in Lymeneuroborreliosis.

Kinase Activity Assays

A number of different assays for kinase activity can be utilized forassaying for active modulators and/or determining specificity of amodulator for a particular kinase or group or kinases. In addition tothe assay mentioned in the Examples below, one of ordinary skill in theart will know of other assays that can be utilized and can modify anassay for a particular application. For example, numerous papersconcerning kinases describe assays that can be used.

In certain embodiments, compounds as disclosed herein are active in anassay measuring BRAF protein kinase activity. In some embodiments, acompound as described herein has an IC₅₀ of less than 1,000 nM, lessthan 500 nM, less than 100 nM, less than 50 nM, less than 20 nM, lessthan 10 nM, less than 5 nM, or less than 1 nM as determined in agenerally accepted BRAF kinase activity assay. In some embodiments, acompound as described herein has an IC₅₀ of less than 1,000 nM, lessthan 500 nM, less than 100 nM, less than 50 nM, less than 20 nM, lessthan 10 nM, less than 5 nM, or less than 1 nM as determined in agenerally accepted mutant BRAF kinase (such as V600A, V600M, V600R,V600E, V600K or V600G) activity assay. In some embodiments the assay formeasuring BRAF kinase activity and/or mutant BRAF kinase (such as V600A,V600M, V600R, V600E, V600K or V600G) activity includes an assay (e.g.,biochemical or cell-bases assays) such as described in Example 13 or anassay well known in the art similar to those described in Example 13.

In some embodiments, compounds as described herein have little or noactivity in an assay measuring activation of the ERK pathway (i.e., instimulating the phosphorylation of ERK 1/2). In some embodiments,compounds as described herein have an EC₅₀ in an ERK activation assaythat is greater than 1 μM; or greater than 2 μM; or greater than 3 μM;or greater than 4 μM; or greater than 5 μM; or greater than 8 μM; orgreater than 10 μM. In certain embodiments, the assay for measuringactivation of the ERK pathway includes an assay (e.g., biochemical orcell-bases assays) such as described in Example 13 or one or more assayswell known in the art for measuring ERK activity similar to thatdescribed in Example 13.

In some embodiments, compounds as described herein are active in anassay measuring BRAF protein kinase activity and/or an assay formeasuring mutant BRAF (such as V600A, V600M, V600R, V600E, V600K orV600G) protein kinase activity, and have little or no activity in anassay measuring activation of the ERK pathway. In some embodiments acompound as described herein has an IC₅₀ of less than 1,000 nM, lessthan 500 nM, less than 100 nM, less than 50 nM, less than 20 nM, lessthan 10 nM, less than 5 nM, or less than 1 nM as determined in agenerally accepted BRAF kinase activity assay (including a mutant BRAFkinase activity assay) and an EC₅₀ in an ERK activation assay that isgreater than 1 μM; or greater than 2 μM; or greater than 3 μM; orgreater than 4 μM; or greater than 5 μM; or greater than 8 μM; orgreater than 10 μM. In some embodiments, a compound as described hereinhas an IC₅₀ of less than 100 nM in a V600A, V600M, V600R, V600E, V600Kor V600G mutant BRAF activity assay and an EC₅₀ of greater than 10 in anERK activation assay.

Compounds as described herein or compounds of formula (I) or anysubgeneric formulas, or a pharmaceutically acceptable salt, a solvate, atautomer or an isomer thereof, or a composition comprising a compound asdescribed herein or a compound of formula (I) or any subgenericformulas, or a pharmaceutically acceptable salt, a solvate, a tautomeror an isomer thereof are effective in pERK inhibition and showessentially no pERK activation in RAS mutant cell line. The degree ofseparation between pERK inhibition and activation (dubbed“phospho-selectivity”) is expressed as the ratio between the mean pERKactivation EC₅₀ of a compound in three RAS mutant cell lines (murinecuSCC cell line B9, human melanoma cell line IPC-298, and humancolorectal carcinoma cell line HCT116) and its mean pERK inhibition IC₅₀in two BRAF^(V600E) melanoma cell lines (A375 and COLO829). FIG. 1a andFIG. 5 demonstrate that a compound of formula (I), for example, compoundA exhibits essentially no pERK activation in RAS mutant cell lines at upto the highest concentration tested.

Compounds as described herein or compounds of formula (I) or anysubgeneric formulas, or a pharmaceutically acceptable salt, a solvate, atautomer or an isomer thereof, or a composition comprising a compound asdescribed herein or a compound of formula (I) or any subgenericformulas, or a pharmaceutically acceptable salt, a solvate, a tautomeror an isomer thereof do not increase pERk level in cells. For example, acompound of formula (I) such as compound A was evaluated in the humanSCC cell line A431 and the human breast carcinoma cell line SKBR3 asthese cells express active MAPK pathway by upstream signals feeding intoRAS (though overexpression of EGFR and HER2, respectively). Unlikevemurafenib, compound A did not increase pERK levels in these cells(FIG. 1b ). As used herein, Paradox Breakers refer to a class of BRAFinhibitory compounds that selectively inhibit mutant BRAF proteinkinase, but does not increase pERK levels in cells.

Compounds as described herein or compounds of formula (I) or anysubgeneric formulas, or a pharmaceutically acceptable salt, a solvate, atautomer or an isomer thereof, or a composition comprising a compound asdescribed herein or a compound of formula (I) or any subgenericformulas, or a pharmaceutically acceptable salt, a solvate, a tautomeror an isomer thereof are effective in inhibit the in vitro growth ofcolorectal cancer cell line COLO205 that expresses BRAF^(V600E) Forexample, compound A inhibited the in vitro growth of two aforementionedmelanoma cell lines (A375 and COLO829) and an additional humancolorectal cancer cell line COLO205 that expresses BRAF^(V600E) Thegrowth inhibition IC₅₀'s of compound A in the three cell lines are lessthan 1 μM. Consistent with this in vitro result, a compound of formula(I), for example, compound A and vemurafenib produced similar antitumoreffects in a subcutaneous COLO205 xenograft model (FIG. 1c ) withmatching doses (25 mg/kg twice daily) and plasma exposures (steady stateAUC=˜200,000 hr*ng/mL). In soft agar, both vemurafenib and its sistercompoundN-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]propane-1-sulfonamide(P-1000) stimulated B9 colony formation at concentrations similar to thegrowth inhibitory IC₅₀'s in A375, COLO829 and COLO205 cells whereascompounds of formula (I) do not (FIG. 1d ). When tested in vivo,subcutaneous B9-tumor growth was accelerated by vemurafenib but not bycompounds of formula (I), for example, compound A administered at thesame dose (FIG. 1e ).

Gene expression changes in B9 cells after exposure to vemurafenib and acompound of formula (I), e.g. compound A were compared. After sorting bydifferential expression scores, a total of 233 Affymetrix Mouse430_2probes (representing 191 uniquely annotated mouse genes) showed morethan 1.9 fold changes in response to overnight incubation of 1 μMvemurafenib (FIG. 2a and Table 4). Several of the best-characterizedmarkers of the MAPK pathway response genes, including Spry2, Fos, andEgr1, were upregulated by vemurafenib. The corresponding human genes areknown to be suppressed by vemurafenib in BRAF^(V600E) mutant humanmelanoma²⁰. Therefore, BRAF inhibitor-stimulated growth of B9 cellsresults from paradoxically increased MAPK signaling and associatedtranscriptional effects in cells with mutant HRAS. In contrast,compounds of formula (I), e.g. compound A had a minimal effect on B9cells: affecting the expression of only a few genes (FIG. 2a and Table4). Of the genes significantly induced by vemurafenib in B9 cells, three(AREG, HB-EGF and TGFα) code for EGFR ligands (amphiregulin,heparin-binding EGF-like growth factor, and transforming growth factorα, respectively) (FIG. 2a ). The upregulation of AREG, HB-EGF and TGFαproteins in B9 cells were confirmed by ELISA (FIG. 2b and FIG. 6). Allthree ligands have been shown to promote SCC (Oshima, G. et al. J CancerRes Clin Oncol 138, 491-499 (2012)). The fourth EGFR ligand that wasabundantly expressed in B9 cells, EREG/epiregulin, was also moderatelyinduced, although the expression of EGFR and other ERBB family membersremained unchanged (FIG. 2a ). not being bound by the theory, theoverexpression of these autocrine growth factors may synergize with thetransforming potential of activated HRAS. In the soft agar assay,exogenous AREG, HB-EGF and TGFα stimulated B9 cell colony formation(FIG. 2c and FIG. 6) whereas the EGFR inhibitor erlotinib antagonizesvemurafenib-induced B9 colony formation (FIG. 2d ). Not being bound bythe theory, these data implicate EGFR signaling as a potential molecularlink between BRAF inhibition and squamous cell carcinogenesis. Incontrast to vemurafenib and consistent with its Paradox Breaker profile,expression of the EGFR ligands was largely unaffected by compounds asdescribed herein, e.g. compounds of formula (I) (FIG. 2a ).

Compounds as described herein or compounds of formula (I′) or (I) or anysubgeneric formulas, or a pharmaceutically acceptable salt, a solvate, atautomer or an isomer thereof, or a composition comprising a compound asdescribed herein or a compound of formula (I) or any subgenericformulas, or a pharmaceutically acceptable salt, a solvate, a tautomeror an isomer thereof effective in modulating RAF dimerization. Based onthe crystal structures of compounds of formula (I′) or (I) in complexwith BRAF^(V600E), the terminal

group occupying the small interior pocket forms closer contact withLeu505 in the pocket. Leu505 is part of the four residues that comprisethe so called regulatory spine of kinases (Taylor, S. S. & Kornev, A. P.Trends Biochem Sci 36, 65-77 (2011). Situated close to the C-terminalend of αC helix, Leu505 is the only residue from the αC helix that makesa direct contact with the inhibitor. FIG. 3a shows N-ethylmethyl moietyforms closer contact with Leu505 in the pocket. Paradoxical MAPK pathwayactivation relies on binding of the RAF inhibitor to one protomer of aRAF homodimer or heterodimer, leading to transactivation of the otherprotomer of the dimer in a RAS-dependent manner (Hatzivassiliou, G. etal. Nature 464, 431-435 (2010); Heidorn, S. J. et al. Cell 140, 209-221(2010); and Poulikakos, P. I., Zhang, C., Bollag, G., Shokat, K. M. &Rosen, N. Nature 464, 427-430 (2010)). The C-terminus of αC helix playsa critical role in RAF dimer formation (Wan, P. T. et al. Cell 116,855-867 (2004); Hatzivassiliou, G. et al. Nature 464, 431-435 (2010);Heidorn, S. J. et al. Cell 140, 209-221 (2010); and Tsai, J. et al. ProcNatl Acad Sci USA 105, 3041-3046 (2008)) and mutations that disrupt thedimer contacts involving the αC helix counteract RAF activation byinhibitors. Without being bound by the theory, the close interaction ofa compound of formula (I), e.g. compound A with Leu505 of the αC helixsuggests the possibility that compounds of formula (I) might modulateRAF dimerization through an allosteric mechanism. In theco-immunoprecipitation-Western blot dimerization assay using celllysates, vemurafenib promoted endogenous BRAF-CRAF heterodimer formationin both B9 and IPC-298 cells whereas the dimer formation was indifferentto the presence of a compound of formula (I), e.g. compound A (FIG. 3b). In two-component biochemical dimerization assays using recombinantRAF kinase domains, a compound of formula (I), e.g. compound A appearedto disrupt the formation of both BRAF-CRAF heterodimers and CRAFhomodimers at mid to high concentration (FIG. 7).

Compounds as described herein or compounds of formula (I) or anysubgeneric formulas, or a pharmaceutically acceptable salt, a solvate, atautomer or an isomer thereof, or a composition comprising a compound asdescribed herein or a compound of formula (I) or any subgenericformulas, or a pharmaceutically acceptable salt, a solvate, a tautomeror an isomer thereof are effective in combating dimerization-mediatedresistance and overcome RAF inhibitor resistance in BRAF fusionscharacterizing pediatric astrocytomas. FIG. 3c shows that compound Ademonstrates minimal shift in pMEK IC₅₀ and modest increase (5 fold) ingrowth inhibition IC₅₀ in C3 cell line.

FIG. 4 demonstrates

group in compounds of formula (I) is critical in reducing pERkactivation. For example, compound P-0352 showed significantly reducedpERK activation in mutant RAS cell lines while preserving the potentinhibitory activity against BRAF^(V600E) cells.

VI. Methods for Treating Conditions Mediated by Kinases

Some embodiments described herein provide a method for treating asubject suffering from or at risk of a protein kinase mediated diseasesor conditions. The method includes administering to the subject aneffective amount of a compound of formula (I) or (I′), or a compound ofany of the subgeneric formulas of formula (I), or a compound asdescribed herein, or a pharmaceutically acceptable salt or a solvate orhydrate thereof, or a composition comprising a compound of formula (I)or a compound of any of the subgeneric formulas of formula (I) or any ofthe compounds described herein, or a pharmaceutically acceptable salt ora solvate or hydrate thereof. In certain embodiments, the methodinvolves administering to the subject an effective amount of any one ormore compound(s) as described herein in combination with one or moreother therapies for the disease or condition. In some embodiments, theprotein kinase is a mutant RAF protein kinase. In some embodiments, themutant RAF protein kinase is a mutant BRAF kinase. In certain instances,the mutant BRAF kinase has a BRAF^(V600) mutation. In one instance, themutant BRAF has a BRAF^(V600E) mutation.

In some embodiments, the diseases or conditions treatable with thecompounds described herein include, but are not limited to,multi-infarct dementia, head injury, brain trauma, brain injury,cognition impairment, spinal cord injury, Alzheimer's disease (AD),Parkinson's disease, seizures and epilepsy; neoplastic diseasesincluding, but not limited to, melanoma, glioma, glioblastomamultiforme, pilocytic astrocytoma, sarcoma, carcinoma (e.g.gastrointestinal, liver, biliary tract, bile duct (cholangiocarcinoma),colorectal, lung, gallbladder, breast, pancreatic, thyroid, renal,ovarian, adrenocortical, prostate), lymphoma (e.g. histiocytic lymphoma)neurofibromatosis, gastrointestinal stromal tumors, acute myeloidleukemia, myelodysplastic syndrome, leukemia, tumor angiogenesis,neuroendocrine tumors such as medullary thyroid cancer, carcinoid, smallcell lung cancer, Kaposi's sarcoma, and pheochromocytoma; pain ofneuropathic or inflammatory origin, including, but not limited to, acutepain, chronic pain, cancer-related pain, and migraine; cardiovasculardiseases including, but not limited to, heart failure, ischemic stroke,cardiac hypertrophy, thrombosis (e.g. thrombotic microangiopathysyndromes), atherosclerosis, and reperfusion injury; inflammation and/orproliferation including, but not limited to, psoriasis, eczema,arthritis and autoimmune diseases and conditions, osteoarthritis,endometriosis, scarring, vascular restenosis, fibrotic disorders,rheumatoid arthritis, inflammatory bowel disease (IBD); immunodeficiencydiseases, including, but not limited to, organ transplant rejection,graft versus host disease, and Kaposi's sarcoma associated with HIV;renal, cystic, or prostatic diseases, including, but not limited to,diabetic nephropathy, polycystic kidney disease, nephrosclerosis,glomerulonephritis, prostate hyperplasia, polycystic liver disease,tuberous sclerosis, Von Hippel Lindau disease, medullary cystic kidneydisease, nephronophthisis, and cystic fibrosis; metabolic disorders,including, but not limited to, obesity; infection, including, but notlimited to Helicobacter pylori, Hepatitis and Influenza viruses, fever,HIV, and sepsis; pulmonary diseases including, but not limited to,chronic obstructive pulmonary disease (COPD) and acute respiratorydistress syndrome (ARDS); genetic developmental diseases, including, butnot limited to, Noonan's syndrome, Costello syndrome,(faciocutaneoskeletal syndrome), LEOPARD syndrome, cardio-faciocutaneoussyndrome (CFC), and neural crest syndrome abnormalities causingcardiovascular, skeletal, intestinal, skin, hair and endocrine diseases;and diseases associated with muscle regeneration or degeneration,including, but not limited to, sarcopenia, muscular dystrophies(including, but not limited to, Duchenne, Becker, Emery-Dreifuss,Limb-Girdle, Facioscapulohumeral, Myotonic, Oculopharyngeal, Distal andCongenital Muscular Dystrophies), motor neuron diseases (including, butnot limited to, amyotrophic lateral sclerosis, infantile progressivespinal muscular atrophy, intermediate spinal muscular atrophy, juvenilespinal muscular atrophy, spinal bulbar muscular atrophy, and adultspinal muscular atrophy), inflammatory myopathies (including, but notlimited to, dermatomyositis, polymyositis, and inclusion body myositis),diseases of the neuromuscular junction (including, but not limited to,myasthenia gravis, Lambert-Eaton syndrome, and congenital myasthenicsyndrome), myopathies due to endocrine abnormalities (including, but notlimited to, hyperthyroid myopathy and hypothyroid myopathy) diseases ofperipheral nerve (including, but not limited to, Charcot-Marie-Toothdisease, Dejerine-Sottas disease, and Friedreich's ataxia), othermyopathies (including, but not limited to, myotonia congenita,paramyotonia congenita, central core disease, nemaline myopathy,myotubular myopathy, and periodic paralysis), and metabolic diseases ofmuscle (including, but not limited to, phosphorylase deficiency, acidmaltase deficiency, phosphofructokinase deficiency, debrancher enzymedeficiency, mitochondrial myopathy, carnitine deficiency, carnitinepalmatyl transferase deficiency, phosphoglycerate kinase deficiency,phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency,and myoadenylate deaminase deficiency). In one embodiment, the diseaseor condition is selected from the group consisting of melanoma, glioma,glioblastoma multiforme, pilocytic astrocytoma, sarcoma, liver cancer,biliary tract cancer, cholangiocarcinoma, colorectal cancer, lungcancer, gallbladder cancer, breast cancer, pancreatic cancer, thyroidcancer, renal cancer, ovarian cancer, adrenocortical cancer, prostatecancer, histiocytic lymphoma, neurofibromatosis, gastrointestinalstromal tumors, acute myeloid leukemia, myelodysplastic syndrome,leukemia, tumor angiogenesis, medullary thyroid cancer, carcinoid, smallcell lung cancer, Kaposi's sarcoma, pheochromocytoma, acute pain,chronic pain, and polycystic kidney disease. In a preferred embodiment,the disease or condition is selected from the group consisting ofmelanoma, glioma, glioblastoma multiforme, pilocytic astrocytoma,colorectal cancer, thyroid cancer, lung cancer, ovarian cancer, prostatecancer, liver cancer, gallbladder cancer, gastrointestinal stromaltumors, biliary tract cancer, cholangiocarcinoma, acute pain, chronicpain, and polycystic kidney disease.

In other embodiments, the diseases or conditions treatable with thecompounds described herein include, but are not limited to, ischemicstroke, brain injury, brain trauma, cerebrovascular ischemia,multi-infarct dementia, head injury, spinal cord injury, Alzheimer'sdisease, Parkinson's disease, amyotrophic lateral sclerosis, dementia,senile chorea, Huntington's disease, neoplastic disease, complicationswith neoplastic disease, chemotherapy-induced hypoxia, gastrointestinalstromal tumors, prostate tumors, mast cell tumors, canine mast celltumors, acute myeloid leukemia, acute lymphocytic leukemia, chronicmyeloid leukemia, chronic lymphocytic leukemia, multiple myeloma,melanoma, mastocytosis, glioma, glioblastoma, astrocytoma,neuroblastoma, sarcomas, sarcomas of neuroectodermal origin,leiomyosarcoma, lung carcinoma, breast carcinoma, pancreatic carcinoma,colon carcinoma, hepatocellular carcinoma, renal carcinoma, carcinoma ofthe female genital tract, squamous cell carcinoma, carcinoma in situ,lymphoma, histiocytic lymphoma, non-Hodgkin's lymphoma, MEN2 syndromes,neurofibromatosis, Schwann cell neoplasia, myelodysplastic syndrome,leukemia, tumor angiogenesis, thyroid cancer, liver cancer, bone cancer,skin cancer, brain cancer, cancer of the central nervous system,pancreatic cancer, lung cancer, small cell lung cancer, non small celllung cancer, breast cancer, colon cancer, bladder cancer, prostatecancer, gastrointestinal tract cancer, cancer of the endometrium,fallopian tube cancer, testicular cancer, ovarian cancer, bone pain,pain of prostate cancer origin, pain of neuropathic origin, pain ofinflammatory origin, acute pain, chronic pain, migraine, cardiovasculardisease, heart failure, cardiac hypertrophy, thrombosis, thromboticmicroangiopathy syndromes, atherosclerosis, reperfusion injury,ischemia, cerebrovascular ischemia, liver ischemia, inflammation,polycystic kidney disease, age-related macular degeneration, rheumatoidarthritis, allergic rhinitis, inflammatory bowel disease, ulcerativecolitis, Crohn's disease, systemic lupus erythematosis, Sjogren'sSyndrome, Wegener's granulomatosis, psoriasis, scleroderma, chronicthyroiditis, Grave's disease, myasthenia gravis, multiple sclerosis,osteoarthritis, endometriosis, dermal scarring, tissue scarring,vascular restenosis, fibrotic disorders, hypereosinophilia, CNSinflammation, pancreatitis, nephritis, atopic dermatitis, hepatitis,immunodeficiency diseases, severe combined immunodeficiency, organtransplant rejection, graft versus host disease, renal disease,prostatic disease, diabetic nephropathy, nephrosclerosis,glomerulonephritis, interstitial nephritis, Lupus nephritis, prostatehyperplasia, chronic renal failure, tubular necrosis,diabetes-associated renal complication, associated renal hypertrophy,type 1 diabetes, type 2 diabetes, metabolic syndrome, obesity, hepaticsteatosis, insulin resistance, hyperglycemia, lipolysis obesity,infection, Helicobacter pylori infection, Influenza virus infection,fever, sepsis, pulmonary diseases, chronic obstructive pulmonarydisease, acute respiratory distress syndrome, asthma, allergy,bronchitis, emphysema, pulmonary fibrosis, genetic developmentaldiseases, Noonan's syndrome, Crouzon syndrome, acrocephalo-syndactylytype I, Pfeiffer's syndrome, Jackson-Weiss syndrome, Costello syndrome,faciocutaneoskeletal syndrome, leopard syndrome, cardio-faciocutaneoussyndrome, neural crest syndrome abnormalities causing cardiovascular,skeletal, intestinal, skin, hair or endocrine diseases, disorders ofbone structure or mineralization, osteoporosis, increased risk offracture, hypercalcemia, bone metastases, pigmented villonodularsynovitis (PVNS), Grave's disease, Hirschsprung's disease, lymphoedema,selective T-cell defect, X-linked agammaglobulinemia, diabeticretinopathy, alopecia, erectile dysfunction, and tuberous sclerosis.

In some embodiments, the disease is a cancer selected from the groupconsisting of melanoma, glioma, glioblastoma, pilocytic astrocytoma,liver cancer, biliary tract cancer, cholangiocarcinoma, colorectalcancer, lung cancer, bladder cancer, gallbladder cancer, breast cancer,pancreatic cancer, thyroid cancer, kidney cancer, ovarian cancer,adrenocortical cancer, prostate cancer, gastrointestinal stromal tumors,medullary thyroid cancer, tumor angiogenesis, acute myeloid leukemia,chronic myelomonocytic leukemia, childhood acute lymphoblastic leukemia,plasma cell leukemia, and multiple myeloma. In certain instances, thedisease is mediated, regulated or modulated by a BRAF V600 mutant, suchas V600A, V600E, V600G, V600K, V600M or V600R mutant. In otherinstances, the diseases are mediated, regulated or modulated byBRAF^(V600/L505H) mutant. In one embodiment, the disease is aBRAF^(V600E) mutant mediated disease. In another embodiment, the diseaseis a BRAF^(V600E/L505H) mutant mediated disease. In one embodiment, thedisease is a cancer, preferably selected from the group consisting ofmelanoma, glioma, glioblastoma multiforme, pilocytic astrocytoma,colorectal cancer, thyroid cancer, lung cancer, ovarian cancer, prostatecancer, liver cancer, gallbladder cancer, gastrointestinal stromaltumors, biliary tract cancer, and cholangiocarcinoma. In one embodiment,the cancer is melanoma, colorectal cancer, thyroid cancer or lungcancer.

In some embodiments, the disclosure provides methods for treating anyBRAF protein kinase mediated disease or condition, including any BRAFmutant kinase mediated disease or condition in an animal subject in needthereof, wherein the method involves administering to the subject inneed thereof an effective amount of any one or more compound(s) asdescribed herein. In certain embodiments, the method involvesadministering to the subject an effective amount of any one or morecompound(s) as described herein in combination with one or more othertherapies for the disease or condition.

In some embodiments, the disclosure provides methods for treating anyBRAF V600 mutant protein kinase, such as V600A, V600E, V600G, V600K,V600M or V600R mutant protein kinase mediated disease or condition in ananimal subject in need thereof, wherein the method involvesadministering to the subject in need thereof an effective amount of anyone or more compound(s) as described herein. In certain embodiments, themethod involves administering to the subject an effective amount of anyone or more compound(s) as described herein in combination with one ormore other therapies for the disease or condition.

In some embodiments, a compound as described herein is a Raf kinaseinhibitor and has an IC₅₀ of less than 500 nM, less than 100 nM, lessthan 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or lessthan 1 nM as determined in a generally accepted Raf kinase activityassay. In some embodiments, a compound as described herein will have anIC₅₀ of less than 500 nM, less than 100 nM, less than 50 nM, less than20 nM, less than 10 nM, less than 5 nM, or less than 1 nM with respectto BRAF, c-Raf-1, or BRAF V600 mutant. In some embodiments, a compoundas described herein will selectively inhibit one or more Raf kinasesrelative to one or more other Raf kinases.

In some embodiments, the disclosure provides a method for inhibiting aBRAF V600 mutant protein kinase, such as V600A, V600E, V600G, V600K,V600M or V600R mutant protein kinase. The method includes contacting acompound of formula (I) or a compound of any of the subgeneric formulasof formula (I), or a compound as described herein, or a pharmaceuticallyacceptable salt or a solvate or hydrate thereof, or a compositioncomprising a compound of formula (I) or a compound of any of thesubgeneric formulas of formula (I) or any of the compounds describedherein, or a pharmaceutically acceptable salt or a solvate or hydratethereof with a cell or a BRAF V600 mutant protein kinase either in vitroor in vivo.

In certain embodiments, the disclosure provides use of a compound offormula (I) or a compound of any of the subgeneric formulas of formula(I), or a compound as described herein, or a pharmaceutically acceptablesalt or a solvate or hydrate thereof, or a composition comprising acompound of formula (I) or a compound of any of the subgeneric formulasof formula (I) or any of the compounds described herein, or apharmaceutically acceptable salt or a solvate or hydrate thereof in themanufacture of a medicament for the treatment of a disease or conditionas described herein. In other embodiments, the invention provides acompound of formula (I) or a compound of any of the subgeneric formulasof formula (I), or a compound as described herein, or a pharmaceuticallyacceptable salt or a solvate or hydrate thereof, or a compositioncomprising a compound of formula (I) or a compound of any of thesubgeneric formulas of formula (I) or any of the compounds describedherein, or a pharmaceutically acceptable salt or a solvate or hydratethereof for use in treating a disease or condition as described herein.

In some embodiments, the disclosure provides a method for suppressing UVinduced cell apoptosis. The method includes contacting a cell with acompound of formula (I) or a compound of any of the subgeneric formulasof formula (I), or a compound as described herein, or a pharmaceuticallyacceptable salt or a solvate or hydrate thereof, or a compositioncomprising a compound of formula (I) or a compound of any of thesubgeneric formulas of formula (I) or any of the compounds describedherein, or a pharmaceutically acceptable salt or a solvate or hydratethereof prior to subject the cell to UV exposure or radiation.

In another aspect, the disclosure provides a method for inhibiting amutant BRAF kinase. The method includes contacting the mutant BRAFkinase in a cell with a compound of formula (I) or a compound of any ofthe subgeneric formulas of formula (I), or a compound as describedherein, or a pharmaceutically acceptable salt or a solvate or hydratethereof, or a composition comprising a compound of formula (I) or acompound of any of the subgeneric formulas of formula (I) or any of thecompounds described herein, or a pharmaceutically acceptable salt or asolvate or hydrate thereof. The contacting can be carried out either invitro or in vivo. In certain embodiments, the mutant BRAF kinase is aBRAF V600 mutant protein kinase, such as V600A, V600E, V600G, V600K,V600M or V600R mutant protein kinase.

In another aspect, the disclosure provides a method for inhibiting amutant BRAF kinase in a subject. The method includes administering tothe subject an effective amount of a compound of formula (I) or acompound of any of the subgeneric formulas of formula (I), or a compoundas described herein, or a pharmaceutically acceptable salt or a solvateor hydrate thereof, or a composition comprising a compound of formula(I) or a compound of any of the subgeneric formulas of formula (I) orany of the compounds as described herein, or a pharmaceuticallyacceptable salt or a solvate or hydrate thereof. In some embodiments,the mutant BRAF is a BRAF^(V600) mutant.

In another aspect, the disclosure provides a method for treating asubject suffering from a melanoma, a thyroid cancer or a colorectalcancer. The method includes administering to the subject in need thereofan effective amount of a compound of formula (I) or a compound of any ofthe subgeneric formulas of formula (I), or a compound as describedherein, or a pharmaceutically acceptable salt or a solvate or hydratethereof, or a composition comprising a compound of formula (I) or acompound of any of the subgeneric formulas of formula (I) or any of thecompounds as described herein, or a pharmaceutically acceptable salt ora solvate or hydrate thereof. In some embodiment, the melanoma is ametastatic melanoma.

Combination Therapy

Protein kinase modulators may be usefully combined with anotherpharmacologically active compound, or with two or more otherpharmacologically active compounds, particularly in the treatment ofcancer. In one embodiment, the composition includes any one or morecompound(s) as described herein along with one or more compounds thatare therapeutically effective for the same disease indication, whereinthe compounds have a synergistic effect on the disease indication. Inone embodiment, the composition includes any one or more compound(s) asdescribed herein effective in treating a cancer and one or more othercompounds that are effective in treating the same cancer, furtherwherein the compounds are synergistically effective in treating thecancer.

In some embodiments, the disclosure provides a composition comprising acompound of any of formulas (I′) or (I) or a compound of any of thesubgeneric formulas of formula (I), or a compound as described herein,or a pharmaceutically acceptable salt or a solvate or hydrate thereof,or a composition comprising a compound of formula (I) or (I′) or acompound of any of the subgeneric formulas of formula (I), for example,formulas (Ia), (Ia-1), (Ia-2), (Ib), (Ib-1), (Ib-2), (Ib-1a), (Ib-1b),(Ic), (Ic-1), (Ic-1a), (Ic-2), (Ic-2a), (Id), (Id-1), (Id-1a), (Id-2),(Id-2a), (Ie), (Ie-1), (Ie-1a), (Ie-2), (Ie-2a), (If), (If-1), (If-2),(If-3), (If-4), (Ig), (Ig-1), (Ig-2), (Ig-3), (Ig-4), (Ih), (Ih-1),(Ih-2), (Ih-3), (Ih-4), (Ij), (Ij-1) or (Ij-2) or any of the compoundsdescribed herein, or a pharmaceutically acceptable salt or a solvate orhydrate thereof, and one or more therapeutic agents. In someembodiments, the one or more therapeutic agents are selected from analkylating agent, including, but not limited to, adozelesin,altretamine, bendamustine, bizelesin, busulfan, carboplatin, carboquone,carmofur, carmustine, chlorambucil, cisplatin, cyclophosphamide,dacarbazine, estramustine, etoglucid, fotemustine, hepsulfam,ifosfamide, improsulfan, irofulven, lomustine, mannosulfan,mechlorethamine, melphalan, mitobronitol, nedaplatin, nimustine,oxaliplatin, piposulfan, prednimustine, procarbazine, ranimustine,satraplatin, semustine, streptozocin, temozolomide, thiotepa,treosulfan, triaziquone, triethylenemelamine, triplatin tetranitrate,trofosphamide, and uramustine; an antibiotic, including, but not limitedto, aclarubicin, amrubicin, bleomycin, dactinomycin, daunorubicin,doxorubicin, elsamitrucin, epirubicin, idarubicin, menogaril, mitomycin,neocarzinostatin, pentostatin, pirarubicin, plicamycin, valrubicin, andzorubicin; an antimetabolite, including, but not limited to,aminopterin, azacitidine, azathioprine, capecitabine, cladribine,clofarabine, cytarabine, decitabine, floxuridine, fludarabine,5-fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate,nelarabine, pemetrexed, azathioprine, raltitrexed, tegafur-uracil,thioguanine, trimethoprim, trimetrexate, and vidarabine; animmunotherapy, including, but not limited to, alemtuzumab, bevacizumab,cetuximab, galiximab, gemtuzumab, panitumumab, pertuzumab, rituximab,tositumomab, trastuzumab, 90 Y ibritumomab tiuxetan, ipilimumab, andtremelimumab; a hormone or hormone antagonist, including, but notlimited to, anastrozole, androgens, buserelin, diethylstilbestrol,exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole,leuprolide, magestrol, raloxifene, tamoxifen, and toremifene; a taxane,including, but not limited to, DJ-927, docetaxel, TPI 287, larotaxel,ortataxel, paclitaxel, DHA-paclitaxel, and tesetaxel; a retinoid,including, but not limited to, alitretinoin, bexarotene, fenretinide,isotretinoin, and tretinoin; an alkaloid, including, but not limited to,demecolcine, homoharringtonine, vinblastine, vincristine, vindesine,vinflunine, and vinorelbine; an antiangiogenic agent, including, but notlimited to, AE-941 (GW786034, Neovastat), ABT-510, 2-methoxyestradiol,lenalidomide, and thalidomide; a topoisomerase inhibitor, including, butnot limited to, amsacrine, belotecan, edotecarin, etoposide, etoposidephosphate, exatecan, irinotecan (also active metabolite SN-38(7-ethyl-10-hydroxy-camptothecin)), lucanthone, mitoxantrone,pixantrone, rubitecan, teniposide, topotecan, and 9-aminocamptothecin; akinase inhibitor, including, but not limited to, vemurafenib,BeiGene-283 (or BGB-283), dabrafenib, LGX818, axitinib (AG 013736),dasatinib (BMS 354825), erlotinib, gefitinib, flavopiridol, imatinibmesylate, lapatinib, motesanib diphosphate (AMG 706), nilotinib(AMN107), seliciclib, sorafenib, sunitinib malate, AEE-788, BMS-599626,UCN-01 (7-hydroxystaurosporine), and vatalanib; a targeted signaltransduction inhibitor including, but not limited to bortezomib,geldanamycin, and rapamycin; a biological response modifier, including,but not limited to, imiquimod, interferon-beta, and interleukin-2; andother chemotherapeutics, including, but not limited to 3-AP(3-amino-2-carboxyaldehyde thiosemicarbazone), altrasentan,aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide,elesclomol, eribulin mesylate (E7389), ixabepilone, lonidamine,masoprocol, mitoguanazone, oblimersen, sulindac, testolactone,tiazofurin, mTOR inhibitors (e.g. temsirolimus, everolimus,deforolimus), PI3K inhibitors (e.g. BEZ235, GDC-0941, XL147, XL765),Cdk4 inhibitors (e.g. PD-332991), Akt inhibitors, Hsp90 inhibitors (e.g.tanespimycin) and farnesyltransferase inhibitors (e.g. tipifarnib); MEKinhibitors (e.g., AS703026, AZD6244 (selumetinib), AZD8330, BIX02188,CI1040 (PD184352), D-87503, GSK1120212 (JTP-74057), GDC0973, PD0325901,PD318088, PD98059, PDEA119 (BAY 869766), TAK-733). Preferably, themethod of treating a cancer involves administering to the subject aneffective amount of a composition including any one or more compound(s)as described herein in combination with a chemotherapeutic agentselected from capecitabine, 5-fluorouracil, carboplatin, dacarbazine,gefitinib, oxaliplatin, paclitaxel, SN-38, temozolomide, vinblastine,bevacizumab, cetuximab, interferon-beta, interleukin-2, or erlotinib. Insome embodiments, a protein kinase modulator, particularly a compound ofany of formula (I) to formula In, or a compound described herein, or apharmaceutically acceptable salt or solvate thereof, as defined above,may be administered simultaneously, sequentially or separately incombination with one or more agents as described above.

In some embodiments, the therapeutic agent is chlorambucil, melphalan,cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine,streptozocin, cisplatin, carboplatin, oxaliplatin, dacarbazine,temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine,gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine,vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide,trabectedin, dactinomycin, doxorubicin, epirubicin, daunorubicin,mitoxantrone, bleomycin, mitomycin, ixabepilone, tamoxifen, fiutamide,gonadorelin analogues, megestrol, prednisone, dexamethasone,methylprednisolone, thalidomide, interferon alfa, leucovorin, sirolimus,temsirolimus, everolimus, afatinib, alisertib, amuvatinib, apatinib,axitinib, bortezomib, bosutinib, brivanib, cabozantinib, cediranib,crenolanib, crizotinib, dabrafenib, dacomitinib, danusertib, dasatinib,dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib,icotinib, imatinib, iniparib, lapatinib, lenvatinib, linifanib,linsitinib, masitinib, momelotinib, motesanib, neratinib, nilotinib,niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib,quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib,saracatinib, saridegib, sorafenib, sunitinib, tasocitinib, telatinib,tivantinib, tivozanib, tofacitinib, trametinib, vandetanib, veliparib,vemurafenib, vismodegib, volasertib, alemtuzumab, bevacizumab,brentuximabvedotin, catumaxomab, cetuximab, denosumab, gemtuzumab,ipilimumab, nimotuzumab, ofatumumab, panitumumab, ramucirumab,rituximab, tositumomab, trastuzumab, or a combination thereof.

In one embodiment, the disclosure provides methods for treating adisease or condition mediated by BRAF kinase, including mutationsthereof, by administering to the subject an effective amount of acomposition including any one or more compound(s) as described herein incombination with one or more other suitable therapies for treating thedisease.

In one embodiment, the disclosure provides methods for treating adisease or condition mediated by BRAF V600 mutant kinases, such asV600A, V600E, V600G, V600K, V600M or V600R mutant kinase, byadministering to the subject an effective amount of a compositionincluding any one or more compound(s) as described herein in combinationwith one or more other suitable therapies for treating the disease. Inone embodiment, the disclosure provides methods for treating a cancermediated by BRAF mutant kinases, such as V600A, V600E, V600G, V600M orV600R mutant by administering to the subject an effective amount of acomposition including any one or more compound(s) as described herein.In one embodiment, the disclosure provides methods for treating a cancermediated by BRAF mutant kinases, such as V600A, V600E, V600G, V600K,V600M or V600R mutant by administering to the subject an effectiveamount of a composition including any one or more compound(s) asdescribed herein in combination with one or more suitable anticancertherapies, such as one or more chemotherapeutic drugs. In one instance,the BRAF mutant kinase is V600A. In another instance, the BRAF mutantkinase is V600E. In yet another instance, the BRAF mutant kinase isV600G. In another instance, the BRAF mutant kinase is V600K. In anotherinstance, the BRAF mutant kinase is V600M. In another instance, the BRAFmutant kinase is V600R.

In one embodiment, the disclosure provides a method of treating a cancerin a subject in need thereof by administering to the subject aneffective amount of a composition including any one or more compound(s)as described herein in combination with one or more other therapies ormedical procedures effective in treating the cancer. Other therapies ormedical procedures include suitable anticancer therapy (e.g. drugtherapy, vaccine therapy, gene therapy, photodynamic therapy) or medicalprocedure (e.g. surgery, radiation treatment, hyperthermia heating, bonemarrow or stem cell transplant). In one embodiment, the one or moresuitable anticancer therapies or medical procedures is selected fromtreatment with a chemotherapeutic agent (e.g. chemotherapeutic drug),radiation treatment (e.g. x-ray, γ-ray, or electron, proton, neutron, orparticle beam), hyperthermia heating (e.g. microwave, ultrasound,radiofrequency ablation), Vaccine therapy (e.g. AFP gene hepatocellularcarcinoma vaccine, AFP adenoviral vector vaccine, AG-858, allogeneicGM-CSF-secretion breast cancer vaccine, dendritic cell peptidevaccines), gene therapy (e.g. Ad5CMV-p53 vector, adenovector encodingMDA7, adenovirus 5-tumor necrosis factor alpha), photodynamic therapy(e.g. aminolevulinic acid, motexafin lutetium), surgery, or bone marrowand stem cell transplantation.

Kit

In another aspect, the disclosure provides kits that include a compoundof any of formulas (I) to (In) or a compound as described herein orcomposition thereof as described herein. In some embodiments, thecompound or composition is packaged, e.g., in a vial, bottle, flask,which may be further packaged, e.g., within a box, envelope, or bag; thecompound or composition is approved by the U.S. Food and DrugAdministration or similar regulatory agency for administration to amammal, e.g., a human; the compound or composition is approved foradministration to a mammal, e.g., a human, for a protein kinase mediateddisease or condition; the disclosure kit may include writteninstructions for use and/or other indication that the compound orcomposition is suitable or approved for administration to a mammal,e.g., a human, for a Raf protein kinase-mediated disease or condition;and the compound or composition may be packaged in unit dose or singledose form, e.g., single dose pills, capsules, or the like.

VII. Examples

The following examples are offered to illustrate, but not to limit thedisclosure.

The synthesis for the compounds described herein and those set forth inTables 1 and 2 may be performed according to methods known in the art,such as in PCT patent publication No. WO 2012/109075, which isincorporated by reference in its entirety. A person of skill in the artis readily capable of preparing all the compounds described herein andthose encompassed by generic formula (I′) or (I) and its sub-genericformulas using the procedures described in the above-mentioned patentapplication and the processes described herein. In addition,abbreviations as used herein have respective meanings as follows:

ATP Adenosine triphosphate BSA Bovine serum albumin cc Cubic centimetercm centimeter DMAP 4-Dimethylaminopyridine DCM Dichloromethane DIPEADiisopropylethylamine DMEM Dulbecco's Modified Eagle Medium DMFDimethylformamide DMSO Dimethylsulfoxide EDTA Ethylenediaminetetraaceticacid eq./equiv. Equivalent ESI Electrospray ionization EtOAc Ethylacetate EtOH Ethanol FBS Fetal bovine serum g Gram h/hrs Hour HPLCHigh-pressure liquid chromatography Hz Hertz i-Pr isopropyl J Joule kgkilligram L Liter LCMS Liquid chromatography-mass spectrometry M MolarMeOH Methanol m/z Mass to charge mg Milligram MHz Mega hertz minsminutes mL/ml Milliliter mol mole mm millimeter mM Millimolar mmolMillimole MS Mass spectrometry MTBE Methyl tert-butyl ether mWMilliwatts nM Nanomolar nm nanometer NMR Nuclear magnetic resonance PBSPhosphate buffered saline PSI/psi Pound-force per square inch R_(f)Retention factor TBAF Tetra-n-butylammonium fluoride THF TetrahydrofuranTLC Thin layer chromatography μL Microliter μM Micromolar

Example 1: Preparation of5-(2-aminopyrimidin-4-yl)-2-tert-butyl-4-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-phenyl]thiazole(P-0352)

Step 1: Synthesis of2-tert-butyl-5-(2-chloropyrimidin-4-yl)-4-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-phenyl]thiazole(2)

Compound 1 was prepared according to the procedure described in U.S.Pat. No. 7,994,185. To a solution of3-[2-tert-butyl-5-(2-chloropyrimidin-4-yl)thiazol-4-yl]-2-fluoro-aniline(1, 102 mg, 0.28 mmol) in dichloromethane (1 mL) was added pyridine (500μL, 6.2 mmol) followed by N-ethyl-N-methyl-sulfamoyl chloride (265 mg,1.68 mmol). The reaction was allowed to stir at 50° C. for 96 hours. Thereaction was worked up by extraction with ethyl acetate and 0.1 MHCl(aq). The product was purified by flash chromatography (5-30% ethylacetate in hexanes) which gave impure material. This material was againpurified by flash chromatography (0.5-6% methanol in DCM). This provided55 mg of2-tert-butyl-5-(2-chloropyrimidin-4-yl)-4-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-phenyl]thiazole(2) that was ˜90% pure and was used in the next step. MS (ESI)[M+H⁺]⁺=484.2. MS (ESI) [M−H⁺]⁻=482.10.

Step 2: Synthesis of5-(2-aminopyrimidin-4-yl)-2-tert-butyl-4-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-phenyl]thiazole(P-0352)

2-tert-butyl-5-(2-chloropyrimidin-4-yl)-4-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-phenyl]thiazole(7, 51 mg, 0.11 mmol) was dissolved in 5 mL of 7 M ammonia in methanolin a sealed reaction vial. The reaction was placed in an oil bath at 80°C. and allowed to stir for 48 hours. All of the volatiles were removedby rotary evaporation. The resulting residue was purified by reversephase HPLC (Buffer A: 5% CH₃CN, 95% water, 0.01% formic acid. Buffer B:95% CH₃CN, 5% water, 0.01% formic acid) to provide 31 mg of5-(2-aminopyrimidin-4-yl)-2-tert-butyl-4-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-phenyl]thiazole(P-0352) MS (ESI) [M+H+]+=465.20.

¹H-NMR Chemical Shift Assignments for P-0352 (DMSO-d₆, 400 MHz)

Chemical Shift Splitting Hydrogen (ppm) Pattern Integration Coupling(Hz) NH₂ 6.77 br s 2 — NH—SO₂— 9.71 br s 1 — Pyrimidine ring 8.04 d 15.1 Benzene ring 7.54 m 1 — Benzene ring 7.30 m 2 — Pyrimidine ring 6.03d 1 5.1 N—CH₂CH₃ 3.06 q 2 7.0 N—CH₃ 2.67 s 3 — —(CH₃)₃ 1.41 s 9 —N—CH₂CH₃ 0.99 t 3 7.0 br s: broad singlet s: singlet d: doublet t:triplet dd: doublet of doublets ddd: doublet of doublet of doublets m:multiplet

Example 2: Preparation ofN-(6-acetamido-3-pyridyl)-2,6-difluoro-3-(pyrrolidin-1-ylsulfonylamino)benzamide(P-2036)

Step 1. Synthesis ofN-(6-acetamido-3-pyridyl)-2,6-difluoro-3-nitro-benzamide. ToN-(5-Amino-pyridin-2-yl)-acetamide (1.53 g, 0.0101 mol) was addedtetrahydrofuran (20 mL, 0.2 mol) followed by pyridine (0.900 mL, 0.0111mol). To this suspension was added a solution of2,6-difluoro-3-nitrobenzoyl chloride (2.24 g, 0.0101 mol) intetrahydrofuran (10 mL, 0.1 mol). After stirring at room temperatureovernight, the reaction was extracted with ethyl acetate and water (withadded HCl). The organic layer was washed with brine, and the combinedaqueous layers were extracted with ethyl acetate. The combined organiclayers were dried over anhydrous magnesium sulfate, filtered andvolatiles removed to give 1.91 g of crude product. This material waspurified by silica gel column chromatography eluting with a gradient of1 to 6% methanol in DCM to give 1.527 g ofN-(6-acetamido-3-pyridyl)-2,6-difluoro-3-nitro-benzamide.MS(ESI)[M+H⁺]⁺=336.9.

Step 2. Synthesis ofN-(6-acetamido-3-pyridyl)-3-amino-2,6-difluoro-benzamide. ToN-(6-acetylamido-pyridin-3-yl)-2,6-difluoro-3-nitro-benzamide (0.500 g,0.00149 mol) in ethanol (30 mL, 0.5 mol) and tetrahydrofuran (85 mL, 1.0mol) was added ˜3 cc of Raney nickel slurry in water (2800). Then, thereaction was placed in a parr hydrogenator under hydrogen at 35 psi.After 2 hours, TLC indicated all starting material consumed, but two newspots observed. The reaction was allowed to continue. After a total of6.5 hrs, TLC shows only one new spot. The reaction was filtered throughcelite and all volatiles removed to give crude material that waspurified by silica gel column chromatography eluting with a gradientfrom 1 to 6% methanol in DCM to give 345 mg ofN-(6-acetamido-3-pyridyl)-3-amino-2,6-difluoro-benzamide.MS(ESI)[M+H⁺]⁺=306.9.

Step 3. Synthesis ofN-(6-acetamido-3-pyridyl)-2,6-difluoro-3-(pyrrolidin-1-ylsulfonylamino)benzamide.To 9.6 mg (0.03 mmol, 1 eq.) ofN-(6-acetamido-3-pyridyl)-3-amino-2,6-difluoro-benzamide was weighedinto a 4 mL vial and combined with 5.1 mg (0.03 mmol, 1 eq.) ofpyrrolidine-1-sulfonyl chloride. This mixture was dissolved in 300 μL ofTHF. To this solution, 25 μL of pyridine was added. The reaction mixturewas shaken at 65° C. for 2 days. All solvents were removed under reducedatmosphere. The crude material was dissolved in 400 μL of dimethylsulfoxide and purified by RP-LCMS to provide 5.3 mg ofN-(6-acetamido-3-pyridyl)-2,6-difluoro-3-(pyrrolidin-1-ylsulfonylamino)benzamide.MS(ESI)[M+H⁺]⁺=440.3.

The following compounds were made in a manner as set forth in Scheme 1.

Compound No. Name MH(+) P-2033N-(6-acetamido-3-pyridyl)-2,6-difluoro-3-(1- 454.3piperidylsulfonylamino)benzamide P-2034N-(6-acetamido-3-pyridyl)-3-(dimethylsulfamoylamino)- 414.32,6-difluoro-benzamide P-2035N-(6-acetamido-3-pyridyl)-3-(cyclopentylsulfonylamino)- 439.12,6-difluoro-benzamide P-2128 N-(6-acetamido-3-pyridyl)-2,6-difluoro-3-456.3 (morpholinosulfonylamino)benzamide

Example 3: Preparation of5-(2-aminopyrimidin-4-yl)-4-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-phenyl]-2-isopropyl-thiazoleand2-tert-butyl-4-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-phenyl]-5-(2-methoxypyrimidin-4-yl)thiazole(P-2089) and2-tert-butyl-4-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-phenyl]-5-(2-methoxypyrimidin-4-yl)thiazole(P-2088)

Step 1. Methyl 3-[(allyloxy)carbonyl]amino-2-fluorobenzoate: To methyl2-fluoro-3-aminobenzoate (15.0 g, 88.7 mmol, 1.0 eq.) and saturatedaqueous sodium bicarbonate (120 mL) in tetrahydrofuran (37.5 mL) at 0°C. was added allyl chloroformate (12.75 g, 106 mmol, 1.19 eq.) dropwise.The reaction was allowed to warm to room temperature slowly. When thereaction was complete as indicated by TLC, it was poured into water (800mL) and extracted with ethyl acetate. The extracts were dried sodiumsulfate, filtered, and concentrated under reduced pressure to providemethyl 3-[(allyloxy)carbonyl]amino-2-fluorobenzoate (24.8 g, 100% yield)as an amber liquid.

Step 2. Synthesis ofallyl(3-(2-(tert-butyl)-5-(2-chloropyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)carbamate: To methyl 3-[(allyloxy)carbonyl]amino-2-fluorobenzoate (10.0g, 39 mmol, 1.0 eq.) in tetrahydrofuran (100 mL) at 0° C. was added a1.0 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran(138 mL, 138 mmol, 3.5 eq.) dropwise. After stirring for 1 hour at 0°C., a solution of 2-chloro-4-methylpyrimidine (6.09 g, 47 mmol, 1.2 eq.)in tetrahydrofuran (100 mL) was added over 20 minutes. The reaction wasallowed to warm to room temperature slowly. When the reaction wascomplete as indicated by LCMS, it was poured into water (1 L). The pHwas adjusted to 7 by the addition of 1N HCl and then NaHCO₃. Thecontents were extracted with ethyl acetate, and the extracts were driedover sodium sulfate, filtered, and concentrated under reduced pressureto provideallyl(3-(2-(tert-butyl)-5-(2-chloropyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)carbamate (12.5 g, 92% yield) as an orange solid.

Step 3. Synthesis ofAllyl(3-(2-(tert-butyl)-5-(2-chloropyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)carbamate:Toally(3-(2-(tert-butyl)-5-(2-chloropyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)carbamate (3.21 g, 9.18 mmol, 1.0 eq.) in dimethylacetamide (35 mL) atroom temperature was added N-bromosuccinimide (1.64 g, 9.21 mmol, 1.0eq.). When the disappearance of starting material was complete asindicated by LCMS, 2,2,2-trimethylthioacetamide (1.3 g, 11.1 mmol, 1.2eq.) was added and the reaction heated at 60° C. overnight. LCMSindicated the reaction was complete. The reaction was poured into water(250 mL) and the contents were extracted with ethyl acetate. Theextracts were dried sodium sulfate, filtered, and concentrated underreduced pressure. The crude product was purified by silica gelchromatography (300 g, 3″ diameter column) eluting with 20% ethylacetate/heptanes to provideallyl(3-(2-(tert-butyl)-5-(2-chloropyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)carbamateas an oil (2.92 g, 70% yield).

Step 4. Synthesis of3-[2-tert-butyl-5-(2-chloropyrimidin-4-yl)thiazol-4-yl]-2-fluoro-aniline:Toally(3-(2-(tert-butyl)-5-(2-chloropyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)carbamate(2.67 g, 5.97 mmol, 1.0 eq.) in dichloromethane (130 mL) and water (2mL) at room temperature was added tri-n-butyltin hydride (1.6 mL, 5.97mmol, 1.0 eq.) then tetrakis(triphenylphoshine)palladium(0) (347 mg, 0.3mmol, 0.05 eq.). After 1.5 hours, the reaction was complete as indicatedby LCMS. Sodium sulfate was added to the reaction. Filtration followedby concentrating under reduced pressure of the filtrate provided thecrude product which was purified by column chromatography (275 g silicagel; 3″ diameter column) eluting with 25% ethyl acetate/heptanes toprovide3-[2-tert-butyl-5-(2-chloropyrimidin-4-yl)thiazol-4-yl]-2-fluoro-aniline(1.04 g, 48% yield) as a yellow solid.

Step 5. Synthesis of2-tert-butyl-5-(2-chloropyrimidin-4-yl)-4-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-phenyl]thiazole.To a solution of3-[2-tert-butyl-5-(2-chloropyrimidin-4-yl)thiazol-4-yl]-2-fluoro-aniline(102 mg, 0.281 mmol) in dichloromethane (1 mL) was added pyridine (254ul, 3.2 mmol) followed by N-ethyl-N-methyl-sulfamoyl chloride (326 mg,2.1 mmol) and dimethylaminopyridine (4 mg, 33 umol). The reaction wasallowed to stir at 40° C. for 72 hours. The reaction was worked up byextraction with ethyl acetate and 0.1 M HCl (aq). The product waspurified by flash chromatography (5-30% ethyl acetate in hexanes) whichgave impure material. This material was again purified by flashchromatography (0.5-6% methanol in DCM) to give 18 mg of2-tert-butyl-5-(2-chloropyrimidin-4-yl)-4-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-phenyl]thiazoleas a white solid. MS (ESI) [M+H+]+=484.2.

Step 6. Synthesis of5-(2-aminopyrimidin-4-yl)-4-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-phenyl]-2-isopropyl-thiazoleand2-tert-butyl-4-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-phenyl]-5-(2-methoxypyrimidin-4-yl)thiazole.To2-tert-butyl-5-(2-chloropyrimidin-4-yl)-4-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-phenyl]thiazole(51 mg, 0.11 mmol) in a vial was added 5 mL of 7M ammonia in methanoland the reaction vial was sealed. The reaction was placed in an oil bathat 80° C. and allowed to stir for 48 hours. All of the volatiles wereremoved by rotary evaporation. The resulting residue was purified byRP-HPLC to provide 31 mg of5-(2-aminopyrimidin-4-yl)-4-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-phenyl]-2-isopropyl-thiazoleas a white solid (MS (ESI) [M+H⁺]⁺=465.20) and 7 mg of2-tert-butyl-4-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-phenyl]-5-(2-methoxypyrimidin-4-yl)thiazoleas a white solid. MS (ESI) [M+H⁺]⁺=480.20.

The following compounds were made according to the procedures set forthin Example 3 and Scheme 2.

Compound No. Name P-20935-(2-aminopyrimidin-4-yl)-2-tert-butyl-4-[3-(dimethylsulfamoylamino)-2-fluoro-phenyl]thiazole P-2106N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-thiazol-4-yl]-2-fluoro-phenyl]butane-2-sulfonamide P-2114N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-thiazol-4-yl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide P-2129(3R)-N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-thiazol-4-yl]-2-fluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide P-2130(3S)-N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-thiazol-4-yl]-2-fluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide P-2131N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-thiazol-4-yl]-2-fluoro-phenyl]azetidine-1-sulfonamide P-2132N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-thiazol-4-yl]-2-fluoro-phenyl]piperidine-1-sulfonamide P-2133N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-thiazol-4-yl]-2-fluoro-phenyl]cyclopropanesulfonamide P-2134N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-thiazol-4-yl]-2-fluoro-phenyl]cyclobutanesulfonamide P-2135N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-thiazol-4-yl]-2-fluoro-phenyl]cyclopentanesulfonamide P-2136N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-thiazol-4-yl]-2-fluoro-phenyl]cyclohexanesulfonamide

Example 3: Synthesis of methylN-[(1S)-2-[[4-[2-tert-butyl-4-[2-fluoro-3-(pyrrolidin-1-ylsulfonylamino)phenyl]thiazol-5-yl]pyrimidin-2-yl]amino]-1-methyl-ethyl]carbamate

The following compounds were made according to the protocol set forth inScheme 2b.

Compound No. Name P-2137 methylN-[(1S)-2-[[4-[4-[3-(azetidin-1-ylsulfonylamino)-2-fluoro-phenyl]-2-tert-butyl-thiazol-5-yl]pyrimidin-2-yl]amino]-1-methyl-ethyl]carbamate P-2138methylN-[(1S)-2-[[4-[2-tert-butyl-4-[2-fluoro-3-[[(3R)-3-fluoropyrrolidin-1-yl]sulfonylamino]phenyl]thiazol-5-yl]pyrimidin-2-yl]amino]-1-methyl-ethyl]carbamate P-2139 methylN-[(1S)-2-[[4-[2-tert-butyl-4-[2-fluoro-3-[[(3S)-3-fluoropyrrolidin-1-yl]sulfonylamino]phenyl]thiazol-5-yl]pyrimidin-2-yl]amino]-1-methyl-ethyl]carbamate P-2140 methylN-[(1S)-2-[[4-[2-tert-butyl-4-[2-fluoro-3-(1-piperidylsulfonylamino)phenyl]thiazol-5-yl]pyrimidin-2-yl]amino]-1-methyl-ethyl]carbamate P-2141 methylN-[(1S)-2-[[4-[2-tert-butyl-4-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-phenyl]thiazol-5-yl]pyrimidin-2-yl]amino]-1-methyl-ethyl]carbamateP-2142 methylN-[(1S)-2-[[4-[2-tert-butyl-4-[3-(cyclopropylsulfonylamino)-2-fluoro-phenyl]thiazol-5-yl]pyrimidin-2-yl]amino]-1-methyl-ethyl]carbamateP-2143 methylN-[(1S)-2-[[4-[2-tert-butyl-4-[3-(cyclobutylsulfonylamino)-2-fluoro-phenyl]thiazol-5-yl]pyrimidin-2-yl]amino]-1-methyl-ethyl]carbamateP-2144 methylN-[(1S)-2-[[4-[2-tert-butyl-4-[3-(cyclopentylsulfonylamino)-2-fluoro-phenyl]thiazol-5-yl]pyrimidin-2-yl]amino]-1-methyl-ethyl]carbamateP-2145 methylN-[(1S)-2-[[4-[2-tert-butyl-4-[3-(cyclohexylsulfonylamino)-2-fluoro-phenyl]thiazol-5-yl]pyrimidin-2-yl]amino]-1-methyl-ethyl]carbamate

Example 4: Synthesis of(3R)—N-[3-[5-(2-aminopyrimidin-4-yl)-2-phenyl-thiazol-4-yl]-2-fluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide

Step 1.Allyl(3-(2-phenyl)-5-(2-chloropyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)carbamate:To ally(3-(2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)carbamate(4.0 g, 11.4 mmol, 1.0 eq.) in dimethylacetamide (40 mL) at roomtemperature was added NBS (2.04 g, 11.4 mmol, 1.0 eq.). When thedisappearance of starting material was complete as indicated by LCMS,thiobenzamide (1.88 g, 13.7 mmol, 1.2 eq.) was added and the reactionheated at 60° C. for 2.5 hours. The reaction was poured into water (350mL) and the contents were extracted with ethyl acetate/THF. The extractswere dried sodium sulfate, filtered, and concentrated under reducedpressure. The crude product was purified via silica gel chromatography(300 g, 3″ diameter column) eluting with 25-50% ethyl acetate/heptane toprovideallyl(3-(2-phenyl)-5-(2-chloropyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)carbamateas a yellow-orange solid (3.3 g, 62% yield).

Step 2.3-[2-Phenyl-5-(2-chloropyrimidin-4-yl)thiazol-4-yl]-2-fluoroaniline: Toally(3-(2-phenyl)-5-(2-chloropyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)carbamate(3.3 g, 7.07 mmol, 1.0 eq.) in dichloromethane (100 mL) and water (2.5mL) at room temperature was added tri-n-butyltin hydride (1.9 mL, 7.07mmol, 1.0 eq.) then tetrakis(triphenylphosphine)palladium(0) (408 mg,0.35 mmol, 0.05 eq.). After 6.25 hours, the reaction was complete byLCMS. Sodium sulfate was added to the reaction. Filtration followed byconcentration under reduced pressure of the filtrate provided the crudeproduct which was purified via column chromatography (250 g silica gel;3″ diameter column) eluting with 20-30% ethyl acetate/heptane then DCMto provide 5 (470 mg, 17% yield) as a yellow solid.

The following compounds were made according to the protocol set forth inScheme 3a.

Compound No. Name P-2146N-[3-[5-(2-aminopyrimidin-4-yl)-2-phenyl-thiazol-4-yl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide P-2147(3S)-N-[3-[5-(2-aminopyrimidin-4-yl)-2-phenyl-thiazol-4-yl]-2-fluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide P-2148N-[3-[5-(2-aminopyrimidin-4-yl)-2-phenyl-thiazol-4-yl]-2-fluoro-phenyl]piperidine-1-sulfonamide P-2149N-[3-[5-(2-aminopyrimidin-4-yl)-2-phenyl-thiazol-4-yl]-2-fluoro-phenyl]cyclopentanesulfonamide P-2150N-[3-[5-(2-aminopyrimidin-4-yl)-2-phenyl-thiazol-4-yl]-2-fluoro-phenyl]cyclohexanesulfonamide

Example 5: Synthesis of methylN-[(1S)-2-[[4-[4-[2-fluoro-3-(pyrrolidin-1-ylsulfonylamino)phenyl]-2-phenyl-thiazol-5-yl]pyrimidin-2-yl]amino]-1-methyl-ethyl]carbamate

The following compounds were made according to the protocol set forth inScheme 3b.

Compound No. Name P-2151 methylN-[(1S)-2-[[4-[4-[3-(azetidin-1-ylsulfonylamino)-2-fluoro-phenyl]-2-phenyl-thiazol-5-yl]pyrimidin-2-yl]amino]-1-methyl-ethyl]carbamateP-2152 methyl N-[(1S)-2-[[4-[4-[2-fluoro-3-[[(3R)-3-fluoropyrrolidin-1-yl]sulfonylamino]phenyl]-2-phenyl-thiazol-5-yl]pyrimidin-2-yl]amino]-1-methyl-ethyl]carbamate P-2153 methylN-[(1S)-2-[[4-[4-[2-fluoro-3-[[(3S)-3-fluoropyrrolidin-1-yl]sulfonylamino]phenyl]-2-phenyl-thiazol-5-yl]pyrimidin-2-yl]amino]-1-methyl-ethyl]carbamate P-2154 methylN-[(1S)-2-[[4-[4-[2-fluoro-3-(1-piperidylsulfonylamino)phenyl]-2-phenyl-thiazol-5-yl]pyrimidin-2-yl]amino]-1-methyl-ethyl]carbamateP-2155 methylN-[(1S)-2-[[4-[4-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-phenyl]-2-phenyl-thiazol-5-yl]pyrimidin-2-yl]amino]-1-methyl-ethyl]carbamateP-2156 methylN-[(1S)-2-[[4-[4-[3-(cyclopropylsulfonylamino)-2-fluoro-phenyl]-2-phenyl-thiazol-5-yl]pyrimidin-2-yl]amino]-1-methyl-ethyl]carbamateP-2157 methylN-[(1S)-2-[[4-[4-[3-(cyclobutylsulfonylamino)-2-fluoro-phenyl]-2-phenyl-thiazol-5-yl]pyrimidin-2-yl]amino]-1-methyl-ethyl]carbamateP-2158 methylN-[(1S)-2-[[4-[4-[3-(cyclopentylsulfonylamino)-2-fluoro-phenyl]-2-phenyl-thiazol-5-yl]pyrimidin-2-yl]amino]-1-methyl-ethyl]carbamateP-2159 methylN-[(1S)-2-[[4-[4-[3-(cyclohexylsulfonylamino)-2-fluoro-phenyl]-2-phenyl-thiazol-5-yl]pyrimidin-2-yl]amino]-1-methyl-ethyl]carbamate

Example 6: Preparation of5-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-4-methyl-7H-pyrrolo[2,3-d]pyrimidine(P-2090)

Step 1.

N-ethyl-N-methyl-sulfamoyl chloride: To sulfuryl chloride (20.63 ml,253.76 mmol) in dichloromethane (500 mL), cooled with ice water, wereadded N-methylethanamine (21.76 ml, 253.76 mmol) and triethylamine(35.39 ml, 253.76 mmol) in dichloromethane (150 mL) over 3 hours. Aftercomplete addition, the reaction was allowed to continue for 1 hour. Thereaction was poured into cold 1 N HCl (50 mL). The organic layer wasseparated and washed with brine and 1N HCl twice, dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated to giveN-ethyl-N-methyl-sulfamoyl chloride 29.5 g (74%) as a light yellow oil.

Step 2.

methyl 3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoate: To methyl3-amino-2-fluoro-benzoate (1.5 g, 8.87 mmol) in pyridine (5 ml, 61.82mmol) was added DMAP (0.11 g, 0.89 mmol) and N-ethyl-N-methyl-sulfamoylchloride (2.8 g, 17.74 mmol). The reaction mixture was stirred at roomtemperature for 4 days. The reaction mixture was diluted with water (+1N citric acid) and extracted with ethyl acetate. The organic layer waswashed with water and brine, dried (MgSO₄) and filtered. The volatileswere removed under vacuum. The crude material was purified by silica gelflash column chromatography using EtOAc/Hexane (0-35% gradient). Thepure fractions were combined and concentrated under vacuum. Thisprovided 1.53 g of methyl3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoate. MS (ESI)[M+H]⁺=291.0.

Step 3.

1-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-3-(hydroxymethyl)benzene. Tomethyl 3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoate (2.03 g, 0.01mol) dissolved in 50 mL of THF and cooled to −20° C. was added 1 MLiAlH₄ in THF (15.03 mL). The reaction mixture became cloudy and slowlywarmed to −10° C. for 2 hrs and was kept between −20° C. and −10° C. for5 hrs. The reaction mixture was quenched with 25 grams Na₂SO₄-10H₂O andallowed to stir for 1 hour. The solid material was removed byfiltration. The filtrate was concentrated under vacuum extracted withEtOAc and water. The organic layer was washed with water and brine,dried (MgSO₄), and filtered. The volatiles were removed under vacuum.The product was purified by silica gel column chromatography usingEtOAc/Hexane (0-80% gradient). The pure fractions were combined andconcentrated under vacuum to provide1-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-3-(hydroxymethyl)benzene(1.72 g). MS (ESI) [M+H]⁺=262.8.

Step 4.

1-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-3-formyl-benzene. To1-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-3-(hydroxymethyl)benzene(1.72 g, 6.56 mmol) was added tetrahydrofuran (80 mL, 1221.54 mmol) and2-iodoxybenzoic acid (45%, 5.3 g, 8.52 mmol). The reaction mixture wasstirred at room temperature overnight. The precipitate was removed byfiltration. The filtrate was collected and concentrated under vacuum.The product was purified by silica gel column chromatography usingEtOAc/Hexane (0-60% gradient). The pure fractions were combined andconcentrated under vacuum to provide1-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-3-formyl-benzene (950 mg).MS(ESI) [M+H]⁺=260.8.

Step 5.

5-iodo-4-methyl-7H-pyrrolo[2,3-d]pyrimidine. To4-methyl-7H-pyrrolo[2,3-d]pyrimidine (1 g, 7.51 mmol) suspended in 30 mLof DCM was added N-iodosuccinimide (1.86 g, 8.26 mmol). The reactionmixture was stirred at room temperature for 2 hrs. The volatiles wereremoved under vacuum. The resulting residue was extracted with ethylacetate and 50% aqueous saturated NaHCO₃. The organic layer was washedwith water and brine, dried (MgSO₄), filtered and the volatiles wereremoved under vacuum. The residue was suspended in acetonitrile andsonicated for 45 mins. The solid material was collected by filtration toprovide 5-iodo-4-methyl-7H-pyrrolo[2,3-d]pyrimidine (1.69 gram).

Step 6.

5-iodo-4-methyl-7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidine. To5-iodo-4-methyl-7H-pyrrolo[2,3-d]pyrimidine (14.17 g, 54.7 mmol)suspended in 250 mL of THF and 10 mL of DMF was added NaH (60%, 3.56 g,82.05 mmol) portion wise. The reaction mixture was stirred at roomtemperature for 30 minutes followed by the addition of4-methylbenzenesulfonyl chloride (15.64 g, 82.05 mmol). The reactionmixture was stirred at room temperature overnight. TLC showed there isno the starting material left along with a new higher R_(f) spot. Thereaction mixture was quenched with 6 N HCl to pH ˜3 followed by theaddition of water and extraction with dichloromethane. The organic layerwas washed with water and brine, dried (MgSO₄) and filtered. Thevolatiles were removed under vacuum and the residue was suspended inacetonitrile and sonicated for 45 mins. The solid material was collectedby filtration and washed with acetonitrile. This provided5-iodo-4-methyl-7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidine (12.99gram). MS (ESI) [M+H]⁺=413.8.

Step 7.

5-[[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-phenyl]-hydroxy-methyl]-4-methyl-7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidine.To 5-iodo-4-methyl-7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidine (0.63 g,1.51 mmol) in THF (5 mL), under an atmosphere of itrogen at −40° C., wasadded a solution of 2 M i-PrMgCl in THF (0.75 ml). The reaction wasallowed to stir at 5° C. in 1 hour. The reaction was cooled to −40° C.,and then 1-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-3-formyl-benzene(0.15 g, 0.58 mmol) was added. The reaction was allowed to warm to roomtemperature over 1 hour. The reaction was poured into water andextracted with ethyl acetate. The organic layer was washed with brine,dried over sodium sulfate, and filtered. The filtrate was concentratedand purified by silica gel column chromatography eluting with a gradientof 20% to 100% ethyl acetate in hexane to give5-[[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-phenyl]-hydroxy-methyl]-4-methyl-7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidine(0.28 g). MS (ESI) [M+H⁺]⁺=548.2.

Step 8.

5-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-4-methyl-7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidine.To5-[[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-phenyl]-hydroxy-methyl]-4-methyl-7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidine(0.28 g, 0.51 mmol) in dichloromethane (40 mL) was added Dess-Martinperiodinane (0.26 g, 0.61 mmol). The reaction was allowed to stir for 10minutes at room temperature. The reaction was concentrated and purifiedusing silica gel column chromatography eluting with 20% to 100% ethylacetate in hexane to give the product5-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-4-methyl-7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidine(0.23 g).

Step 9.

5-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-4-methyl-7H-pyrrolo[2,3-d]pyrimidine.To5-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-4-methyl-7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidine(0.23 g, 0.42 mmol) in methanol (50 ml) was added potassium hydroxide(0.2 g, 3.56 mmol). The reaction was allowed to stir for 60 minutes atroom temperature. The reaction was concentrated and purified usingsilica gel column chromatography eluting with 2% to 15% methanol inmethylene chloride to give5-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-4-methyl-7H-pyrrolo[2,3-d]pyrimidine(P-2090) (71.8 mg). MS (ESI) [M+H+]+=392.1.

The following compounds were made according to the synthetic protocolset forth in Scheme 4.

Compound No. Name MH(+) P-20265-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-7H- 381.9pyrrolo[2,3-d]pyrimidine P-2027N-[2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5- 421.1carbonyl)phenyl]cyclohexanesulfonamide P-2028N-[2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5- 407.1carbonyl)phenyl]cyclopentanesulfonamide P-2029N-[2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5- 408.3carbonyl)phenyl]pyrrolidine-1-sulfonamide P-2030N-[2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5- 393.1carbonyl)phenyl]cyclobutanesulfonamide P-2031N-[2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5- 424.3carbonyl)phenyl]morpholine-4-sulfonamide P-2032N-[2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5- 390.3carbonyl)phenyl]pyrrolidine-1-sulfonamide P-2076N-[2-fluoro-3-(4-methyl-7H-pyrrolo[2,3-d]pyrimidine-5- 402.0 (MH−)carbonyl)phenyl]pyrrolidine-1-sulfonamide P-2078N-[3-(4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-2- 428.1(MH−) fluoro-phenyl]pyrrolidine-1-sulfonamide P-20865-[2-fluoro-3-[[methyl(propyl)sulfamoyl]amino]benzoyl]-4- 406.2methyl-7H-pyrrolo[2,3-d]pyrimidine P-2087 4-cyclopropyl-5-[2-fluoro-3-432.2 [[methyl(propyl)sulfamoyl]amino]benzoyl]-7H-pyrrolo[2,3-d]pyrimidine P-20914-cyclopropyl-5-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro- 418.2benzoyl]-7H-pyrrolo[2,3-d]pyrimidine

Example 7: Preparation of4-(cyclopropylmethylamino)-5-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-7H-pyrrolo[2,3-d]pyrimidine(P-2048)

Step 1.

methylN-[3-[[4-(cyclopropylmethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-hydroxy-methyl]-2,4-difluoro-phenyl]carbamate.A mixture of [N-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(0.62 g, 3.29 mmol), methyl N-(2,4-difluoro-3-formyl-phenyl)carbamate(0.92 g, 4.28 mmol), and potassium hydroxide (0.55 g, 9.88 mmol) inmethanol (9 mL) was stirred at room temperature for 16 hours. Thereaction mixture was neutralized with 1N HCl (aq) to pH 3 and extractedwith ethyl acetate (2 times). The combined organic layers were washedwith brine, dried over sodium sulfate, filtered, and concentrated. Thecrude material was purified by silica gel column chromatography elutingwith methanol in dichloromethane. This provided methylN-[3-[[4-(cyclopropylmethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-hydroxy-methyl]-2,4-difluoro-phenyl]carbamate(0.448 g). MS(ESI) [M+H+]+=403.9

Step 2.

methylN-[3-[4-(cyclopropylmethylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]-2,4-difluoro-phenyl]carbamate.To methylN-[3-[[4-(cyclopropylmethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-hydroxy-methyl]-2,4-difluoro-phenyl]carbamate(446 mg, 1.11 mmol) in dimethyl sulfoxide (4 ml) was added2-iodoxybenzoic acid (0.894 g). The resulting solution was stirredovernight. The reaction was poured into water and extracted with ethylacetate (2 times). The combined organic layers were washed with brine,dried over sodium sulfate, filtered, and concentrated. The crudematerial was purified by silica gel flash chromatography eluting withmethanol and dichloromethane. This provided 443 mg of methylN-[3-[4-(cyclopropylmethylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]-2,4-difluoro-phenyl]carbamate.MS(ESI) [M+H+]+=402.3.

Step 3.

(3-amino-2,6-difluoro-phenyl)-[4-(cyclopropylmethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone.To methylN-[3-[4-(cyclopropylmethylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]-2,4-difluoro-phenyl]carbamate(443 mg, 1.1 mmol) in tetrahydrofuran (4.5 ml), was added 5 M of sodiumhydroxide in water (5.5 ml). The mixture was refluxed overnight. Afterthe reaction mixture cooled to room temperature, it was neutralized with6N HCl (aq). The resulting mixture was extracted with ethyl acetate (2times). The combined organic layers were washed with brine, dried oversodium sulfate, filtered, and concentrated. The crude material waspurified by silica gel flash chromatography eluting with methanol anddichloromethane. This provided 0.185 g of(3-amino-2,6-difluoro-phenyl)-[4-(cyclopropylmethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone.MS(ESI) [M+H+]+=344.3.

Step 4.

4-(cyclopropylmethylamino)-5-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-7H-pyrrolo[2,3-d]pyrimidine(P-2048). To(3-amino-2,6-difluoro-phenyl)-[4-(cyclopropylmethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone(500 mg, 1.46 mmol) dissolved in pyridine (5 ml) was addedN,N-dimethylsulfamoyl chloride (230 mg, 1.60 mmol). The reaction wasstirred at room temperature for 3 days. The solvent was then removedunder vacuum and the resulting material was purified by silica gel flashchromatography eluting a gradient of methanol in dichloromethane (0-2%methanol). MS ESI [M+H⁺]⁺=450.9.

The following compounds were made according to the synthetic protocolset forth in Scheme 4b.

Compound No. Name MH(+) P-2037N-[2,4-difluoro-3-[4-(isopropylamino)-7H-pyrrolo[2,3- 438.0d]pyrimidine-5-carbonyl]phenyl]propane-2-sulfonamide P-2038N-[2,4-difluoro-3-[4-(isopropylamino)-7H-pyrrolo[2,3- 479.0d]pyrimidine-5-carbonyl]phenyl]piperidine-1-sulfonamide P-2039N-[2,4-difluoro-3-[4-(isopropylamino)-7H-pyrrolo[2,3- 478.0d]pyrimidine-5-carbonyl]phenyl]cyclohexanesulfonamide P-2040N-[2,4-difluoro-3-[4-(isopropylamino)-7H-pyrrolo[2,3- 464.0d]pyrimidine-5-carbonyl]phenyl]cyclopentanesulfonamide P-2041N-[2,4-difluoro-3-[4-(isopropylamino)-7H-pyrrolo[2,3- 465.0d]pyrimidine-5-carbonyl]phenyl]pyrrolidine-1-sulfonamide P-20425-[3-(diethylsulfamoylamino)-2,6-difluoro-benzoyl]-4- 467.5(isopropylamino)-7H-pyrrolo[2,3-d]pyrimidine P-2043N-[2,4-difluoro-3-[4-(isopropylamino)-7H-pyrrolo[2,3- 450.0d]pyrimidine-5-carbonyl]phenyl]cyclobutanesulfonamide P-2044N-[2,4-difluoro-3-[4-(isopropylamino)-7H-pyrrolo[2,3- 481.0d]pyrimidine-5-carbonyl]phenyl]morpholine-4-sulfonamide P-20455-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-4- 439.0(isopropylamino)-7H-pyrrolo[2,3-d]pyrimidine P-2046N-[3-[4-(cyclopropylmethylamino)-7H-pyrrolo[2,3- 448.0d]pyrimidine-5-carbonyl]-2,4-difluoro- phenyl]cyclopropanesulfonamideP-2047 N-[3-[4-(cyclopropylmethylamino)-7H-pyrrolo[2,3- 450.0d]pyrimidine-5-carbonyl]-2,4-difluoro-phenyl]propane-2- sulfonamideP-2049 N-[3-[4-(cyclopropylmethylamino)-7H-pyrrolo[2,3- 490.5d]pyrimidine-5-carbonyl]-2,4-difluoro- phenyl]cyclohexanesulfonamideP-2050 N-[3-[4-(cyclopropylmethylamino)-7H-pyrrolo[2,3- 476.5d]pyrimidine-5-carbonyl]-2,4-difluoro- phenyl]cyclopentanesulfonamideP-2051 N-[3-[4-(cyclopropylmethylamino)-7H-pyrrolo[2,3- 478.0d]pyrimidine-5-carbonyl]-2,4-difluoro-phenyl]pentane-2- sulfonamideP-2052 4-(cyclopropylmethylamino)-5-[3-(diethylsulfamoylamino)- 479.02,6-difluoro-benzoyl]-7H-pyrrolo[2,3-d]pyrimidine P-2053N-[3-[4-(cyclopropylmethylamino)-7H-pyrrolo[2,3- 462.5d]pyrimidine-5-carbonyl]-2,4-difluoro- phenyl]cyclobutanesulfonamideP-2054 N-[3-[4-(cyclopropylmethylamino)-7H-pyrrolo[2,3- 493.1d]pyrimidine-5-carbonyl]-2,4-difluoro-phenyl]morpholine-4- sulfonamideP-2055 N-[3-[4-(cyclopropylmethylamino)-7H-pyrrolo[2,3- 477.1d]pyrimidine-5-carbonyl]-2,4-difluoro-phenyl]pyrrolidine-1- sulfonamideP-2056 N-[3-[4-(cyclopropylmethylamino)-7H-pyrrolo[2,3- 464.3d]pyrimidine-5-carbonyl]-2,4-difluoro-phenyl]butane-2- sulfonamideP-2057 N-[3-[4-(cyclopropylmethylamino)-7H-pyrrolo[2,3- 459.4d]pyrimidine-5-carbonyl]-2-fluoro-phenyl]pyrrolidine-1- sulfonamideP-2058 N-[3-[4-(cyclopropylmethylamino)-7H-pyrrolo[2,3- 492.5d]pyrimidine-5-carbonyl]-2,4-difluoro-phenyl]tetrahydropyran-4-sulfonamide P-20614-(cyclopropylmethylamino)-5-[3- 465.1[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-7H-pyrrolo[2,3-d]pyrimidine P-20625-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-4- 407.1(methylamino)-7H-pyrrolo[2,3-d]pyrimidine P-20634-(cyclopropylamino)-5-[3- 433.2[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-7H-pyrrolo[2,3-d]pyrimidine P-2064 4-(cyclopropylmethylamino)-5-[3- 447.0[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-7H-pyrrolo[2,3-d]pyrimidine P-20655-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-4- 475.0(2,2,2-trifluoroethylamino)-7H-pyrrolo[2,3-d]pyrimidine P-20665-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-4- 435.2(propylamino)-7H-pyrrolo[2,3-d]pyrimidine P-20675-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-4- 435.4(isopropylamino)-7H-pyrrolo[2,3-d]pyrimidine P-20684-[(4,4-difluorocyclohexyl)amino]-5-[3- 511.1[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-7H-pyrrolo[2,3-d]pyrimidine P-20695-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-4- 465.1[(2-hydroxy-2-methyl-propyl)amino]-7H-pyrrolo[2,3- d]pyrimidine P-2070N-[3-[4-(cyclopropylamino)-7H-pyrrolo[2,3-d]pyrimidine-5- 445.4carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide P-2071N-[2-fluoro-3-[4-(methylamino)-7H-pyrrolo[2,3- 419.3d]pyrimidine-5-carbonyl]phenyl]pyrrolidine-1-sulfonamide P-20724-(cyclobutylamino)-5-[3-[[ethyl(methyl)sulfamoyl]amino]- 447.32-fluoro-benzoyl]-7H-pyrrolo[2,3-d]pyrimidine P-20735-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-4- 451.3(2-methoxyethylamino)-7H-pyrrolo[2,3-d]pyrimidine P-20745-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-4- 477.1[[(2S)-tetrahydrofuran-2-yl]methylamino]-7H-pyrrolo[2,3- d]pyrimidineP-2075 5-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-4- 477.0(tetrahydropyran-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidine P-2077N-[2-fluoro-3-[4-(2,2,2-trifluoroethylamino)-7H-pyrrolo[2,3- 487.2d]pyrimidine-5-carbonyl]phenyl]pyrrolidine-1-sulfonamide P-20794-[[(1R)-1-cyclopropylethyl]amino]-5-[3- 461.1[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-7H-pyrrolo[2,3-d]pyrimidine P-2080 4-[[(1S)-1-cyclopropylethyl]amino]-5-[3-461.5 [[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-7H-pyrrolo[2,3-d]pyrimidine P-2081N-[3-[4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidine-5- 459.4carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide P-2082N-[2-fluoro-3-[4-[[(2S)-tetrahydrofuran-2-yl]methylamino]- 489.47H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]phenyl]pyrrolidine- 1-sulfonamideP-2083 N-[2-fluoro-3-[4-(tetrahydropyran-4-ylamino)-7H- 489.1pyrrolo[2,3-d]pyrimidine-5-carbonyl]phenyl]pyrrolidine-1- sulfonamideP-2084 N-[2-fluoro-3-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidine-5- 419.9carbonyl)phenyl]pyrrolidine-1-sulfonamide P-20925-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-4- 406.1 (MH−)methoxy-7H-pyrrolo[2,3-d]pyrimidine P-2094N-[3-[4-[[(1R)-1-cyclopropylethyl]amino]-7H-pyrrolo[2,3- 473.4d]pyrimidine-5-carbonyl]-2-fluoro-phenyl]pyrrolidine-1- sulfonamideP-2095 N-[3-[4-[(2,2-dimethyl-1,3-dioxolan-4-yl)methylamino]-7H- 519.1pyrrolo[2,3-d]pyrimidine-5-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide P-2096N-[3-[4-(2,3-dihydroxypropylamino)-7H-pyrrolo[2,3- 479.1d]pyrimidine-5-carbonyl]-2-fluoro-phenyl]pyrrolidine-1- sulfonamideP-2097 1-[[5-[2-fluoro-3-(pyrrolidin-1-ylsulfonylamino)benzoyl]- 489.07H-pyrrolo[2,3-d]pyrimidin-4- yl]amino]cyclopropanecarboxylic acidP-2098 N-[2-fluoro-3-[4-[(3-hydroxycyclobutyl)methylamino]-7H- 489.1pyrrolo[2,3-d]pyrimidine-5-carbonyl]phenyl]pyrrolidine-1- sulfonamideP-2099 5-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]- 453.24-(propylamino)-7H-pyrrolo[2,3-d]pyrimidine P-21005-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]- 469.14-(2-methoxyethylamino)-7H-pyrrolo[2,3-d]pyrimidine P-21014-(cyclobutylamino)-5-[3-[[ethyl(methyl)sulfamoyl]amino]- 465.02,6-difluoro-benzoyl]-7H-pyrrolo[2,3-d]pyrimidine P-2102N-[3-[4-(2-aminoethylamino)-7H-pyrrolo[2,3-d]pyrimidine- 448.05-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide P-2103 ethyl2-[[5-[2-fluoro-3-(pyrrolidin-1- 491.2ylsulfonylamino)benzoyl]-7H-pyrrolo[2,3-d]pyrimidin-4- yl]amino]acetateP-2104 N-[2-fluoro-3-[4-(2-methoxyethylamino)-7H-pyrrolo[2,3- 463.2d]pyrimidine-5-carbonyl]phenyl]pyrrolidine-1-sulfonamide P-2105N-[2-fluoro-3-[4-(3-methoxypropylamino)-7H-pyrrolo[2,3- 477.1d]pyrimidine-5-carbonyl]phenyl]pyrrolidine-1-sulfonamide P-2107 methyl2-[[5-[2-fluoro-3-(pyrrolidin-1- 533.2ylsulfonylamino)benzoyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-4-methyl-pentanoate P-2108N-[2-fluoro-3-[4-[(3-hydroxy-3-methyl-butyl)amino]-7H- 491.2pyrrolo[2,3-d]pyrimidine-5-carbonyl]phenyl]pyrrolidine-1- sulfonamideP-2109 2-[[5-[2-fluoro-3-(pyrrolidin-1-ylsulfonylamino)benzoyl]- 463.07H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]acetic acid P-2110N-[2-fluoro-3-[4-(2-morpholinoethylamino)-7H-pyrrolo[2,3- 518.1d]pyrimidine-5-carbonyl]phenyl]pyrrolidine-1-sulfonamide P-2111N-[2-fluoro-3-[4-(3-morpholinopropylamino)-7H- 532.1pyrrolo[2,3-d]pyrimidine-5-carbonyl]phenyl]pyrrolidine-1- sulfonamideP-2112 N-[2-fluoro-3-[4-(3,3,3-trifluoropropylamino)-7H- 501.0pyrrolo[2,3-d]pyrimidine-5-carbonyl]phenyl]pyrrolidine-1- sulfonamideP-2113 N-[3-[4-[[3-(dimethylamino)-2,2-dimethyl-propyl]amino]- 518.17H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide P-21155-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-4- 465.1(3-methoxypropylamino)-7H-pyrrolo[2,3-d]pyrimidine P-21165-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]- 483.14-(3-methoxypropylamino)-7H-pyrrolo[2,3-d]pyrimidine P-21175-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]- 453.04-(isopropylamino)-7H-pyrrolo[2,3-d]pyrimidine P-21184-[[(1R)-1-cyclopropylethyl]amino]-5-[3- 479.0[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-7H-pyrrolo[2,3-d]pyrimidine P-21195-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]- 495.34-(tetrahydropyran-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidine

Example 8: Preparation ofN-(3-(2-(tert-butyl)-5-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-4-yl)-2-fluorophenyl)pyrrolidine-1-sulfonamide(P-2121)

Step 1. 1-(2-Fluoro-3-nitrophenyl)ethanone:Bis(triphenylphosphine)palladium(II) dichloride (1.6 g, 2.28 mmol, 0.05equiv) was added to a solution of 1-bromo-2-fluoro-3-nitrobenzene (10.0g, 45.6 mmol, 1 equiv) and tri-n-butyl(1-ethoxyvinyl)stannane (15.4 mL,45.6 mmol, 1 equiv) in dioxane (100 mL). The resulting turbid solutionwas heated at 90° C. for 4 hours during which time a dark brown solutionformed. After TLC (30% MTBE/heptane) confirmed complete conversion, thereaction was cooled to room temperature. A saturated solution of KF (100mL) and ethyl acetate (100 mL) were added and the biphasic mixture wasstirred for 1 hour and filtered through Celite, washing with ethylacetate. The organic layer was separated and dried over Na₂SO₄,filtered, and evaporated yielding the crude enol ether product as abrown oil. The crude product was dissolved in THF (50 mL) and 2 N HCl(50 mL) was added. The reaction was stirred at room temperature for 1.5hours. The reaction was then saturated with NaCl and extracted with MTBE(2×150 mL). The organic layer was washed with brine (1×300 mL), driedover Na₂SO₄, filtered, and evaporated yielding crude material that waspurified by silica gel column chromatography eluting with 0-40% ethylacetate/heptanes gradient. Fractions containing product were evaporatedunder reduced pressure yielding compound1-(2-Fluoro-3-nitrophenyl)ethanone (7.1 g, 86% yield) as a yellow oil.

Step 2. 2-(tert-Butyl)-4-(2-fluoro-3-nitrophenyl)thiazole: Copper (II)bromide (33.9 g, 152 mmol, 1.9 equiv) was suspended/dissolved in ethylacetate (75 mL) with mechanical stirring.1-(2-Fluoro-3-nitrophenyl)ethanone (14.4 g, 80.0 mmol, 1 equiv) was thenadded as a solution in CHCl₃ (75 mL) and the reaction was heated toreflux for 24 hours. The reaction was cooled to room temperature andfiltered through a short plug of silica gel washing with ethyl acetate.The filtrate was evaporated leaving crude2-bromo-1-(2-fluoro-3-nitrophenyl) ethanone which was dissolved indimethylacetamide (150 mL) and 2,2-dimethylpropanethioamide (10.3 g,88.0 mmol, 1 equiv). The reaction was stirred at room temperature for1.5 hours. The reaction was heated to 60° C. for 2 hours, cooled to roomtemperature, and diluted with water (300 mL). The mixture was extractedwith 15% MTBE in heptane (2×200 mL). The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered, and evaporated. Thecrude material was purified by silica gel column chromatography elutingwith 0-15% ethyl acetate in heptane. Fractions containing product wereevaporated yielding 2-(tert-Butyl)-4-(2-fluoro-3-nitrophenyl)thiazole(15.6 g, 70% yield over 2 steps) as an off-white solid.

Step 3. 5-Bromo-2-(tert-butyl)-4-(2-fluoro-3-nitrophenyl)thiazole:Bromine (5.8 mL, 113 mmol, 1.8 equiv) was added to a solution of2-(tert-Butyl)-4-(2-fluoro-3-nitrophenyl)thiazole (17.6 g, 63 mmol, 1equiv) in chloroform (250 mL). The reaction was heated at reflux for 18hours. Trifluoroacetic acid (1 mL) was added and reaction was heated atreflux for an additional 24 hours. The reaction was then cooled to roomtemperature, diluted with DCM (250 mL), and washed with saturatedaqueous Na₂S₂O₃ (1×500 mL) and saturated aqueous NaHCO₃ (1×250 mL). Theorganic layer was dried over Na₂SO₄, filtered, and evaporated. Theresulting material was purified by silica gel column chromatographyeluting with 0-20% MTBE in heptane yielding additional5-Bromo-2-(tert-butyl)-4-(2-fluoro-3-nitrophenyl)thiazole (1.2 g, 18.6 gtotal, 82% yield).

Step 4. 3-(5-Bromo-2-(tert-butyl)thiazol-4-yl)-2-fluoroaniline: To asolution of 5-Bromo-2-(tert-butyl)-4-(2-fluoro-3-nitrophenyl)thiazole(18.6 g, 51.8 mmol, 1 equiv) in ethyl acetate/THF (150 mL/150 mL) wasadded SnCl₂ dihydrate (40.9 g, 181 mmol, 3.5 equiv) and the reaction washeated to 60° C. for 2.5 hours. The reaction was cooled to roomtemperature and quenched by the slow addition of saturated aqueousNaHCO₃ (500 mL). The biphasic mixture was filtered through Celite (veryslow) washing with ethyl acetate. The filtrate was transferred to aseparatory funnel and the phases separated. The organic phase was washedwith brine (1×250 mL), dried over Na₂SO₄, filtered, and evaporatedleaving a yellow oil. Heptane (90 mL) and MTBE (10 mL) were added todissolve the oil. Crystallization of3-(5-Bromo-2-(tert-butyl)thiazol-4-yl)-2-fluoroaniline provided (13.1 g)with an additional (2.0 g) isolated from the mother liquor by silica gelcolumn chromatography (15.1 g total, 88% yield).

Step 5.N-(3-(5-Bromo-2-(tert-butyl)thiazol-4-yl)-2-fluorophenyl)pyrrolidine-1-sulfonamide:A solution of 3-(5-Bromo-2-(tert-butyl)thiazol-4-yl)-2-fluoroaniline(13.5 g, 41 mmol, 1 equiv), pyridine (10 mL, 123 mmol, 3 equiv), andpyrrolidine-1-sulfonyl chloride (21 g, 123 mmol, 3 equiv) inacetonitrile (230 mL) was heated at 60° C. for 18 hours. The reactionwas cooled to room temperature and the solvent evaporated. The residuewas partitioned between ethyl acetate (300 mL) and 1 N HCl (300 mL). Thephases were separated and the organic layer was washed with brine (1×300mL), dried over Na₂SO₄, filtered, and evaporated yielding a brown oil.Heptane (90 mL) and MTBE (10 mL). Crystallization ofN-(3-(5-Bromo-2-(tert-butyl)thiazol-4-yl)-2-fluorophenyl)pyrrolidine-1-sulfonamideprovided (8.45 g, 46% yield) as an off-white solid.

Step 6.N-(3-(2-(tert-butyl)-5-(2-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-4-yl)-2-fluorophenyl)pyrrolidine-1-sulfonamide:A mixture of1-(benzenesulfonyl)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine(1.1 g, 1.381 mmol, ˜50% purity),N-(3-(5-bromo-2-(tert-butyl)thiazol-4-yl)-2-fluorophenyl)pyrrolidine-1-sulfonamide(0.426 g, 0.921 mmol), potassium carbonate (0.382 g, 2.76 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.075 g,0.092 mmol) in dioxane (12.27 mL) and water (6.14 mL) was heated at 90°C. for several hours. Upon cooling, the reaction mixture diluted withwater and extracted with ethyl acetate. The organic layer was separatedand concentrated under reduced pressure to give the crude product whichwas purified by silica gel column chromatography eluting with 0-100%ethyl acetate/heptane to giveN-(3-(2-(tert-butyl)-5-(2-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-4-yl)-2-fluorophenyl)pyrrolidine-1-sulfonamide(0.60 g, 0.918 mmol, 100% yield) as a yellow solid.

Step 7.N-(3-(2-(tert-butyl)-5-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-4-yl)-2-fluorophenyl)pyrrolidine-1-sulfonamide(P-2121): To a solution ofN-(3-(2-(tert-butyl)-5-(2-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-4-yl)-2-fluorophenyl)pyrrolidine-1-sulfonamide(0.60 g, 0.918 mmol) in THF (9.18 mL) was added TBAF trihydrate (1.448g, 4.59 mmol) and stirred 40° C. for 4 hours. Additional TBAF trihydrate(1.448 g, 4.59 mmol) as added and the mixture was stirred overnight. Themixture was diluted with water/brine and ethyl acetate and the layerswere separated. The organic layer was concentrated under reducedpressure to give crude product which was purified by silica gel columnchromatography eluting with 0-10% methanol/DCM and triturated withMTBE/heptane and filtered washing with heptane and dried in a vacuumoven to giveN-(3-(2-(tert-butyl)-5-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-4-yl)-2-fluorophenyl)pyrrolidine-1-sulfonamide(0.18 g, 0.350 mmol, 38% yield) as an off-white solid. MS (ESI)[M+H⁺]⁺=514.2.

The following compounds were made according to the synthetic protocolset forth in scheme 5.

Compound No. Name MH(+) P-2120N-[3-[2-tert-butyl-5-(1H-pyrrolo[2,3-b]pyridin-4- 500.0yl)thiazol-4-yl]-2-fluoro-phenyl]pyrrolidine-1- sulfonamide P-2126N-[3-[2-tert-butyl-5-(2-methyl-3H-imidazo[4,5- 515.1b]pyridin-7-yl)thiazol-4-yl]-2-fluoro-phenyl]pyr- rolidine-1-sulfonamide

Example 9: Preparation ofN-(3-(2-(tert-butyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)pyrrolidine-1-sulfonamide(P-2122)

Step 1.N-(3-(2-(tert-butyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-4-yl)-2-fluorophenyl)pyrrolidine-1-sulfonamide:ToN-(3-(5-Bromo-2-(tert-butyl)thiazol-4-yl)-2-fluorophenyl)pyrrolidine-1-sulfonamide(1.50 g, 3.24 mmol) in dry THF (32.4 mL) was added sodium hydride 60%(0.162 g, 4.22 mmol) and the mixture was stirred at −78° C. for 30minutes. Then n-butyllithium 2.5M hexanes (1.946 mL, 4.87 mmol) wasadded dropwise and the mixture was stirred at −78° C. for 30 minutes.Then, i-propylpinacol borate (3.31 mL, 16.22 mmol) was added and wasallowed to warm to room temperature overnight. The reaction was pouredinto 1% aqueous HCl/brine and then extracted with ethyl acetate. Theorganic layer was separated and concentrated under reduced pressure togiveN-(3-(2-(tert-butyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-4-yl)-2-fluorophenyl)pyrrolidine-1-sulfonamide(1.65 g, 2.267 mmol, 69.9% yield) as an oil along with ˜30% of thecorresponding 5-protio thiazole which was used directly in the nextstep.

Step 2.N-(3-(2-(tert-butyl)-5-(7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)pyrrolidine-1-sulfonamide:7-(benzenesulfonyl)-4-chloro-pyrrolo[2,3-d]pyrimidine (0.142 g, 0.483mmol),N-(3-(2-(tert-butyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-4-yl)-2-fluorophenyl)pyrrolidine-1-sulfonamide(0.551 g, 0.725 mmol), potassium carbonate (0.200 g, 1.450 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.039 g,0.048 mmol) in dioxane (6.45 mL) and water (3.22 mL) were heated at 100°C. for several hours. Upon cooling, the reaction mixture diluted withwater and extracted with ethyl acetate. The organic layer was separatedand concentrated under reduced pressure to give the crude product whichwas purified by silica gel column chromatography eluting with 0-100%ethyl acetate/heptane to giveN-(3-(2-(tert-butyl)-5-(7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)pyrrolidine-1-sulfonamide(0.20 g, 0.312 mmol, 65% yield) as a clear semi-solid.

Step 3.N-(3-(2-(tert-butyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)pyrrolidine-1-sulfonamide(P-2122): To a solution ofN-(3-(2-(tert-butyl)-5-(7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)pyrrolidine-1-sulfonamide(0.20 g, 0.312 mmol) in THF (3.12 mL) was added TBAF trihydrate (1.083g, 3.43 mmol) and stirred 40° C. overnight. The mixture was diluted withwater/brine and ethyl acetate and the layers were separated. The organiclayer was concentrated under reduced pressure to give crude productwhich was purified by silica gel column chromatography eluting with0-10% methanol/DCM and triturated with MTBE/heptane and filtered washingwith heptane and dried in a vacuum oven to giveN-(3-(2-(tert-butyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)pyrrolidine-1-sulfonamide(0.080 g, 0.160 mmol, 51% yield) as an off-white solid. MS (ESI)[M+H⁺]⁺=501.0.

The following compounds were made according to the synthetic protocolset forth in Scheme 6.

Compound # Name MH(+) P-2123N-[3-[2-tert-butyl-5-(6-methyl-7H-pyrrolo[2,3- 515.1d]pyrimidin-4-yl)thiazol-4-yl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide P-2124N-[3-[2-tert-butyl-5-(8-methyl-9H-purin-6- 516.3yl)thiazol-4-yl]-2-fluoro-phenyl]pyrrolidine-1- sulfonamide P-2125N-[3-[2-tert-butyl-5-(9H-purin-6-yl)thiazol-4- 502.2yl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide

Example 10:N-(5-chloro-3-(5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluorophenyl)pyrrolidine-1-sulfonamide(P-2180)

Step 1.(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)(5-chloro-2-fluoro-3-nitrophenyl)methanone:To 5-chloro-2-fluoro-3-nitrobenzoic acid (20 g, 91 mmol) was addedthionyl chloride (66.5 mL, 911 mmol). The reaction was heated at 80° C.overnight and allowed to cool to room temperature. The volatiles wereremoved under reduced pressure and then azeotroped from toluene severaltimes to give 2-fluoro-3-nitro-benzoyl chloride as an oil which was useddirectly. 5-bromo-1H-pyrrolo[2,3-b]pyridine (12 g, 60.9 mmol) andaluminum chloride (48.7 g, 365 mmol) in nitromethane (152 mL) wereallowed to stir at room temperature for 1 hour. Then2-fluoro-3-nitro-benzoyl chloride (21.74 g, 91 mmol) in nitromethane(152 mL) was added and the mixture was heated at 50° C. for 3 days.After cooling to 0° C., the reaction was quenched with methanol (˜200mL) resulting in a precipitate. The mixture was diluted with water (˜200mL) and then filtered. The crude product was triturated with MTBE andfiltered washing with additional MTBE to give(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)(5-chloro-2-fluoro-3-nitrophenyl)methanoneas a brown solid.

Step 2.(3-amino-5-chloro-2-fluorophenyl)(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone:To(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)(5-chloro-2-fluoro-3-nitrophenyl)methanone(24.27 g, 60.9 mmol) in ethyl acetate (761 mL) and THF (761 mL) wastreated portion wise with tin(II) chloride dihydrate (48.1 g, 213 mmol)while heating to 60° C. and held at this temperature overnight. Aftercooling to room temperature, the reaction mixture was quenched with halfsat. aqueous sodium bicarbonate and filtered through Celite washing thecake with ethyl acetate. The layers were separated and the organic layerwas concentrated under reduced pressure to give(3-amino-5-chloro-2-fluorophenyl)(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone(8 g, 21.70 mmol, 35.6% yield) as a tan solid.

Step 3.(3-(3-amino-5-chloro-2-fluorobenzoyl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-1-yl)(2,6-dichlorophenyl)methanone:To (3-amino-5-chloro-2-fluorophenyl)(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methanon (8 g, 21.70 mmol) in THF(87 mL) was added DMAP (0.265 g, 2.170 mmol), DIPEA (7.56 mL, 43.4 mmol)and 2,6-dichlorobenzoyl chloride (3.42 mL, 23.87 mmol) and the reactionwas stirred at 25° C. overnight. The reaction mixture was diluted withwater and extracted with ethyl acetate. The organic layer was separatedand concentrated under reduced pressure and the crude product wasdissolved in DCM and purified by silica gel column chromatographyeluting with 0-40% ethyl acetate/heptane and triturated with heptane andfiltered to give(3-(3-amino-5-chloro-2-fluorobenzoyl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-1-yl)(2,6-dichlorophenyl)methanone(5.1 g, 9.42 mmol, 43.4% yield) as a yellow solid.

Step 4.(3-(3-amino-5-chloro-2-fluorobenzoyl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-1-yl)(2,6-dichlorophenyl)methanone:A mixture of(3-(3-amino-5-chloro-2-fluorobenzoyl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-1-yl)(2,6-dichlorophenyl)methanone(4 g, 7.39 mmol), (2-cyclopropylpyrimidin-5-yl)boronic acid (2.422 g,14.77 mmol), powdered potassium carbonate (3.06 g, 22.16 mmol) andbis(triphenylphosphine)palladium(II) dichloride (0.259 g, 0.369 mmol) indioxane (39.4 mL) and water (19.70 mL) was heated at 90° C. for 1 hour.Upon cooling, the reaction mixture diluted with water and extracted withethyl acetate. The organic layer was separated and concentrated underreduced pressure to give the crude product purified by silica gel columnchromatography eluting with 0-100% ethyl acetate/heptane to give(3-(3-amino-5-chloro-2-fluorobenzoyl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-1-yl)(2,6-dichlorophenyl)methanone(4.3 g, 7.40 mmol, 100% yield) as a yellow solid.

Step 5.N-(5-chloro-3-(5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluorophenyl)pyrrolidine-1-sulfonamide(P-2180): To(3-(3-amino-5-chloro-2-fluorobenzoyl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-1-yl)(2,6-dichlorophenyl)methanone(0.250 g, 0.430 mmol) in acetonitrile (2.460 mL) was added DMAP (5.26mg, 0.043 mmol), pyridine (0.174 mL, 2.152 mmol) andpyrrolidine-1-sulfonyl chloride (0.292 g, 1.722 mmol) and the reactionwas heated at 70° C. for 2 days. The reaction mixture was concentratedunder reduced pressure and then was partitioned between water and ethylacetate. The organic layer was concentrated under reduced pressure togive the crude product which was dissolved in a mixture of MeOH (2.87mL) and dimethylacetamide (1.433 mL) and treated with ammonia 7 M MeOH(0.307 mL, 2.150 mmol) and heated at 50° C. overnight. The volatileswere removed under reduced pressure and the residue was partitionedbetween ethyl acetate and water/brine. The organic layer wasconcentrated under reduced pressure to give the crude product which wasdissolved in THF (4 mL) and purified by reverse phase (55 g) columnchromatography eluting with 0-100% acetonitrile/water and trituratedwith DCM/heptane and filtered to giveN-(5-chloro-3-(5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluorophenyl)pyrrolidine-1-sulfonamide(0.050 g, 0.092 mmol, 21.5% yield) as an off-white solid. MS (ESI)[M+H⁺]⁺=540.9

The following compounds were made according to the synthetic protocolset forth in Scheme 7.

Compound No. Name MH(+) P-2171N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3- 525.3carbonyl]-2,5-difluoro-phenyl]pyrrolidine-1-sulfonamide P-2172(3R)-N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3- 543.3b]pyridine-3-carbonyl]-2,5-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide P-21735-(2-cyclopropylpyrimidin-5-yl)-3-[3-(dimethylsulfamoylamino)- 499.32,5-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine P-2174(3R)-N-[5-chloro-3-[5-(2-cyclopropylpyrimidin-5-yl)-1H- 559.2pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide P-21753-[5-chloro-3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-5-(2- 515.2cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine P-2176N-[5-chloro-3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3- 545.1b]pyridine-3-carbonyl]-2-fluoro-phenyl]-2,2,5,5-tetradeuterio-pyrrolidine-1-sulfonamide P-2177N-[5-chloro-3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3- 549b]pyridine-3-carbonyl]-2-fluoro-phenyl]-2,2,3,3,4,4,5,5-octadeuterio-pyrrolidine-1-sulfonamide P-2178(3R)-N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3- 593.1b]pyridine-3-carbonyl]-2-fluoro-5-(trifluoromethyl)phenyl]-3-fluoro-pyrrolidine-1-sulfonamide P-2179N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3- 575.1carbonyl]-2-fluoro-5-(trifluoromethyl)phenyl]pyrrolidine-1- sulfonamide

The following compounds were prepared according to the protocol setforth in Scheme 7 using the appropriate 7-azaindole in place of8-bromo-7-azaindole.

Compound # Name MH(+) P-2001N-[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3- 409.9carbonyl)phenyl]propane-2-sulfonamide P-20023-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-4-methoxy-1H- 411.1pyrrolo[2,3-b]pyridine P-2003N-[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3- 437.1carbonyl)phenyl]pyrrolidine-1-sulfonamide P-20043-[3-(diethylsulfamoylamino)-2,6-difluoro-benzoyl]-4-methoxy-1H- 439.1pyrrolo[2,3-b]pyridine P-2005N-[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3- 449.9carbonyl)phenyl]cyclohexanesulfonamide P-2006N-[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3- 423.9carbonyl)phenyl]butane-2-sulfonamide P-20074-chloro-3-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-1H- 415.1pyrrolo[2,3-b]pyridine P-2008N-[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro- 425.9phenyl]cyclobutanesulfonamide P-2009N-[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3- 437.9carbonyl)phenyl]pentane-2-sulfonamide P-2010N-[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3- 421.9carbonyl)phenyl]cyclobutanesulfonamide P-20114-chloro-3-[3-(diethylsulfamoylamino)-2,6-difluoro-benzoyl]-1H- 443.1pyrrolo[2,3-b]pyridine P-20124-cyano-3-[3-(diethylsulfamoylamino)-2,6-difluoro-benzoyl]-1H- 433.9pyrrolo[2,3-b]pyridine P-2013N-[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro- 413.9phenyl]propane-2-sulfonamide P-2014N-[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro- 453.9phenyl]cyclohexanesulfonamide P-2015N-[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro- 439.9phenyl]cyclopentanesulfonamide P-2016N-[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro- 427.9phenyl]butane-2-sulfonamide P-2017N-[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro- 405.1phenyl]propane-2-sulfonamide P-2018N-[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro- 445.1phenyl]cyclohexanesulfonamide P-2019N-[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro- 431.9phenyl]pyrrolidine-1-sulfonamide P-2020N-[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro- 419.1phenyl]butane-2-sulfonamide P-2021N-[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro- 417.5phenyl]cyclobutanesulfonamide P-2022N-[3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro- 447.9phenyl]morpholine-4-sulfonamide P-2023N-[2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3- 453.1carbonyl)phenyl]morpholine-4-sulfonamide P-2024N-[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro- 457.1phenyl]morpholine-4-sulfonamide P-2025N-[3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro- 441.1phenyl]pyrrolidine-1-sulfonamide

Example 11: Synthesis of methylN-[(1S)-2-[[4-[4-[5-chloro-2-fluoro-3-(1-piperidylsulfonylamino)phenyl]-1-isopropyl-pyrazol-3-yl]pyrimidin-2-yl]amino]-1-methyl-ethyl]carbamate

Step 1. Starting material prepared according to PCT publication No.WO/2011/025927, which is incorporated herein by reference in itsentirety for all purposes.

The following compounds were prepared according to the syntheticprotocol set forth in Scheme 8.

Compound No. Name MH(+) P-2001 methylN-[(1S)-2-[[4-[4-[5-chloro-2-fluoro-3-(pyrrolidin-1- 409.9ylsulfonylamino)phenyl]-1-isopropyl-pyrazol-3-yl]pyrimidin-2-yl]amino]-1-methyl-ethyl]carbamate P-2002 methylN-[(1S)-2-[[4-[4-[5-chloro-2-fluoro-3-[[(3R)-3- 411.1fluoropyrrolidin-1-yl]sulfonylamino]phenyl]-1-isopropyl-pyrazol-3-yl]pyrimidin-2-yl]amino]-1-methyl-ethyl]carbamate P-2003 methylN-[(1S)-2-[[4-[4-[5-chloro-2-fluoro-3-[[(3S)-3- 437.1fluoropyrrolidin-1-yl]sulfonylamino]phenyl]-1-isopropyl-pyrazol-3-yl]pyrimidin-2-yl]amino]-1-methyl-ethyl]carbamate P-2004 methylN-[(1S)-2-[[4-[4-[3-(azetidin-1-ylsulfonylamino)-5- 439.1chloro-2-fluoro-phenyl]-1-isopropyl-pyrazol-3-yl]pyrimidin-2-yl]amino]-1-methyl-ethyl]carbamate P-2005 methylN-[(1S)-2-[[4-[4-[5-chloro-3- 449.9[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-phenyl]-1-isopropyl-pyrazol-3-yl]pyrimidin-2-yl]amino]-1-methyl-ethyl]carbamate P-2006methyl N-[(1S)-2-[[4-[4-[5-chloro-3-(diethylsulfamoylamino)-2- 423.9fluoro-phenyl]-1-isopropyl-pyrazol-3-yl]pyrimidin-2-yl]amino]-1-methyl-ethyl]carbamate P-2007 methylN-[(1S)-2-[[4-[4-[5-chloro-3-(dimethylsulfamoylamino)- 415.12-fluoro-phenyl]-1-isopropyl-pyrazol-3-yl]pyrimidin-2-yl]amino]-1-methyl-ethyl]carbamate P-2008 methylN-[(1S)-2-[[4-[4-[5-chloro-3-(cyclohexylsulfonylamino)- 425.92-fluoro-phenyl]-1-isopropyl-pyrazol-3-yl]pyrimidin-2-yl]amino]-1-methyl-ethyl]carbamate P-2009 methylN-[(1S)-2-[[4-[4-[5-chloro-3-(cyclopentylsulfonylamino)- 437.92-fluoro-phenyl]-1-isopropyl-pyrazol-3-yl]pyrimidin-2-yl]amino]-1-methyl-ethyl]carbamate P-2010 methylN-[(1S)-2-[[4-[4-[5-chloro-3-(cyclobutylsulfonylamino)-2- 421.9fluoro-phenyl]-1-isopropyl-pyrazol-3-yl]pyrimidin-2-yl]amino]-1-methyl-ethyl]carbamate P-2011 methylN-[(1S)-2-[[4-[4-[5-chloro-3-(cyclopropylsulfonylamino)- 443.12-fluoro-phenyl]-1-isopropyl-pyrazol-3-yl]pyrimidin-2-yl]amino]-1-methyl-ethyl]carbamate

Example 12: Synthesis ofN-[3-[4-(cyclopropylmethylamino)-5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide(P-2060)

Step 1.N-[3-[4-(cyclopropylmethylamino)-5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide.ToN-[2,4-difluoro-3-(5-fluoro-4-iodo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl]pyrrolidine-1-sulfonamide(95 mg, 0.17 mmol) in isopropyl alcohol (2 ml) was addedcyclopropylmethanamine (49.11 mg, 0.69 mmol). The resulting solution wasstirred at 90° C. overnight. The reaction mixture was concentrated undervacuum and purified by silica gel flash chromatography eluting withEtOAc/Hexane (0-65% gradient). Fractions containing desired product werepooled and the product was further purified by preparative HPLC. Thepure fractions were combined to provide 6.5 mgN-[3-[4-(cyclopropylmethylamino)-5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide.MS (ESI) [M+H]⁺=494.4.

Compounds of formula (I′) or (I) or a compound of any of the subgenericformulas of formula (I), for example, formulas (Ia), (Ia-1), (Ia-2),(Ib), (Ib-1), (Ib-2), (Ib-1a), (Ib-1b), (Ic), (Ic-1), (Ic-1a), (Ic-2),(Ic-2a), (Id), (Id-1), (Id-1a), (Id-2), (Id-2a), (Ie), (Ie-1), (Ie-1a),(Ie-2), (Ie-2a), (If), (If-1), (If-2), (If-3), (If-4), (Ig), (Ig-1),(Ig-2), (Ig-3), (Ig-4), (Ih), (Ih-1), (Ih-2), (Ih-3), (Ih-4), (Ij),(Ij-1) or (Ij-2), or any of the compounds as described herein can beprepared according to the protocols set forth in Examples 1-12. Forexample, compounds listed in Tables 1 and 2, such as compounds P-2001 toP-2183 were prepared according to the protocols set forth in Examples 1to 12. The ¹H NMR and mass spectroscopy data were consistent with thestructures of the compounds.

Example 13: Compound Properties

While the inhibitory activity of the compounds on any Raf kinase isimportant to their activity in treating of disease, the compoundsdescribed herein show favorable properties that provide advantages as apharmaceutical as well.

Assays for biochemical and cell based activity are known in the art, forexample, as described in PCT publication WO 2007/002433, the disclosureof which is hereby incorporated by reference as it relates to suchassays. For example, the biochemical activity IC₅₀ values are determinedwith respect to inhibition of BRAF V600E kinase activity or p-Erk kinaseactivity, where inhibition of phosphorylation of a peptide substrate ismeasured as a function of compound concentration. Compounds to be testedare diluted in dimethyl sulfoxide to a concentration of 0.1 mM. Theseare serially diluted 15 μL into 30 μL of dimethyl sulfoxide seven timesin 96 well plates for a total of 8 dilution points, and for eachdilution point 1 μL is added to a well of an assay plate. Plates areprepared such that each well in a 384 well plate contains 1 μL ofcompound in 10 μL volume with 0.1 nanograms Raf enzyme (i.e. any ofBRAF, c-Raf-1 or BRAF V600E, Upstate Biotechnology or prepared bymethods known to one of skill in the art), 50 mM HEPES, pH 7.0, 50 mMNaCl, 2 mM MgCl₂, 1 mM MnCl₂, 0.01% Tween-20, 1 mM DTT, and 100 nMbiotin-MEK1 as substrate. The reaction is started with addition of 10 μLof 200 μM ATP (i.e. final 100 μM ATP). After incubation of the kinasereaction for 45 minutes at room temperature, 5 μL/well of Stop Solutionis added (25 mM Hepes pH 7.5, 100 mM EDTA, 0.01% BSA with donor beads(Streptavidin coated beads, Perkin Elmer), acceptor beads (Protein Acoated, Perkin Elmer), and anti-phosphor MEK1/2 antibody (CellSignal),each at final concentration 10 μg/mL). The plates are incubated for 3hours at room temperature and read on Envision reader (Perkin Elmer).Phosphorylation of Mek1 results in binding of theanti-phosphor-MEK1/2antibody and association of the donor and acceptorbeads such that signal correlates with kinase activity. The signalversus compound concentration is used to determine the IC₅₀.

Compounds are assessed in a variety of cell based assays. For examplehuman cell lines with BRAF V600E mutation (A375 melanoma, SKMEL3melanoma, and COLO205 colon adenocarcinoma), as well as tumorigenic celllines with wild-type BRAF (SW620 colon adenocarcinoma) or with Rasmutations (SKMEL2 melanoma and IPC298 melanoma). Similar assays may beused to assess additional tumorigenic cell lines with Ras mutations,including, but not limited to, M202, M207, M243, M244, M296, 5117,HCT116, HCT15, DLD1, MiaPaCa, A549, NCI-H23, NCI-H460, HOP62, MDA-MB231,Hs-578T, HL60, MOLT-4, and CCRF-CEM.

On day 1, cells are counted, then centrifuged in a conical tube for 5minutes at 1000 rpm. The supernatant is removed and cells arere-suspended as follows:

-   -   SW620 (ATCC catalog # CCL-27): resuspended in Leibovitz's L-15        medium, 2 mM L-glutamine, 10% fetal bovine serum to 6×10⁴        cells/mL.    -   A375 (ATCC catalog # CRL-1619): resuspend in Dulbecco's modified        Eagle's medium, 4 mM L-glutamine, 4.5 g/L D-glucose, 10% fetal        bovine serum to 6×10⁴ cells/mL.    -   COLO205 (ATCC catalog # CCL-222): resuspend in RPMI 1640, 2 mM        L-glutamine, 1.5 g/L sodium bicarbonate, 4.5 g/L D-glucose, 10        mM HEPES, 1.0 mM sodium pyruvate, 10% fetal bovine serum to        6×10⁴ cells/mL.    -   SKMEL2 (ATCC catalog # HTB-68): resuspend in Minimum Eagle        essential medium, 2 mM L-glutamine, 1.5 g/L sodium bicarbonate,        0.1 mM non-essential amino acids, 1.0 mM sodium pyruvate, 10%        fetal bovine serum to 6×10⁴ cells/mL.    -   SKMEL3 (ATCC catalog # HTB-69): resuspend in McCoy's 5A medium,        1.5 mM L-glutamine, 15% fetal bovine serum to 6×10⁴ cells/mL.    -   IPC298 (DSMZ catalog # ACC 251): resuspend in RPMI 1640, 2 mM        L-glutamine, 10% fetal bovine serum to 6×10⁴ cells/mL.

The cells are plated, 50 μL in each well of a 96-well dish (Corning3610) and incubated at 37° C. in 5% CO₂ overnight, cells plated to afinal concentration of cells as follows:

-   -   SW620: 5,000 cells per well.    -   A375: 2,000 cells per well.    -   COLO205: 2,000 cells per well.    -   SKMEL2: 2,000 cells per well.    -   SKMEL3: 3,000 cells per well.    -   IPC298: 2,000 cells per well.

On day 2, compound at a maximum concentration of 5 mM is seriallydiluted 1:3 (e.g. 10 μL with 30 μL dimethyl sulfoxide) for a total of 8point titration with DMSO as a control. A 1 μL aliquot of each dilutionpoint and control is added to 249 μL growth media and 50 μL is added toa well containing cells, providing 10 μM compound at the maximumconcentration point. The cells are incubated for 3 days at 37° C. in 5%CO₂.

On day 5, ATPlite 1 step Luminescence Assay System (Perkin Elmer#6016739) is brought to room temperature along with the cell cultures.ATPlite is added 25 μL to each well, shake for 2 minutes, and the cellsare incubated at room temperature for 10 minutes, then luminescence isread on Safire reader. The measured luminescence correlates directlywith cell number, such that the reading as a function of compoundconcentration is used to determine the IC₅₀ value.

B9 is a squamous cell carcinoma cell line expressing activated HRAS thatwas isolated from a DMBA/TPA-induced mouse model of skin carcinogenesis(Stoler, et al. The Journal of Cell Biology, 1993, 122(5), 1103-17).IPC-298 is a human melanoma cell line that expresses activated NRAS(Aubert, et al. International Journal of Cancer, 1993, 54(5), 784-92).To determine whether compounds induce phosphorylated ERK and MEK, cellsare plated in a 96-well dish and treated with an 8-point titration ofcompound for one hour at 37° C. The media is then removed and the cellsare incubated with lysis buffer containing protease and phosphataseinhibitors. Phosphorylated ERK and MEK in the resulting lysates isdetected using AlphaScreen™ technology. To detect phosphorylated ERK,cell lysates are incubated with streptavidin-coated donor beads,anti-mouse IgG acceptor beads, a biotinylated anti-ERK1/2 rabbitantibody, and a mouse antibody that recognizes ERK1/2 only when it isphosphorylated on Thr202 and Tyr204. The biotinylated ERK1/2 antibodywill bind to both the streptavidin-coated donor beads and to ERK1/2(regardless of its phosphorylation state), and the phospho-ERK1/2antibody will bind to the acceptor beads and to ERK1/2 that isphosphorylated at Thr202/Tyr204. Excitation of the beads with laserlight at 680 nm produces singlet oxygen, which is rapidly quenchedunless the beads are in close proximity. When ERK is phosphorylated,both antibodies can bind the same protein, bringing the donor andacceptor beads into close proximity, producing a signal that can bemeasured at 580 nm. MEK phosphorylation is detected using a similarapproach, only with antibodies directed against total MEK1/2 and MEK1/2that is phosphorylated at Ser217 and Ser221.

The assay data for the compounds in Tables 1 and 2 has been disclosed inPCT patent publication No. WO 2012/109075, which is incorporated hereinby reference in its entirety for all purposes.

The following table provides data indicating the BRAF V600E biochemicalinhibitory activity, B9 and IPC-298_P-ERK cell activation activity,A375_P-ERK cell growth inhibitory activity for exemplary compounds asdescribed herein. In the table below, inhibitory activity in the BRAFmutant assays is provided as follows: +++=0.0001 μM<IC₅₀<1 μM; ++=1μM<IC₅₀<10 μM; +=10 μM<IC₅₀.

Biochemical Cell activity Cell activity activity Compound (IC₅₀ μM)(EC₅₀ μM) (IC₅₀ μM) number V600E IPC-298_P-ERK B9_pERK A375 P-2001+++ >10 >10 + P-2002 +++ >10 >10 +++ P-2003 +++ >10 >10 +++ P-2004++ >10 >10 + P-2005 +++ >10 >10 ++ P-2006 +++ >10 >10 +++ P-2007+++ >10 >10 +++ P-2008 +++ >10 >10 +++ P-2009 +++ >10 >10 ++ P-2010+++ >10 >10 ++ P-2011 +++ >10 >10 ++ P-2012 +++ >10 >10 ++ P-2013 ++++++ P-2014 +++ >10 >10 +++ P-2015 +++ >10 >10 + P-2016 +++ >10 >10 +++P-2017 +++ >10 >10 +++ P-2018 +++ >10 >10 + P-2019 +++ >10 >10 +++P-2020 +++ >10 >10 +++ P-2021 +++ >10 >10 + P-2022 +++ >10 >10 +++P-2023 +++ >10 >10 ++ P-2024 +++ >10 >10 +++ P-2025 +++ >10 >10 +++P-2026 ++ >10 >10 + P-2027 +++ >10 >10 +++ P-2028 +++ >10 >10 + P-2029+++ >10 >10 +++ P-2030 ++ >10 >10 ++ P-2031 ++ >10 >10 + P-2032+++ >10 >10 +++ P-2033 +++ >10 >10 + P-2034 +++ >10 >10 ++ P-2035+++ >10 >10 ++ P-2036 ++ >10 >10 ++ P-2037 +++ >10 >10 +++ P-2038+++ >10 >10 +++ P-2039 +++ >10 >10 +++ P-2040 +++ >10 >10 +++ P-2042+++ >10 >10 +++ P-2043 ++ >10 >10 ++ P-2044 +++ >10 >10 +++ P-2045+++ >10 >10 +++ P-2047 +++ +++ P-2048 +++ >10 +++ P-2049 +++ >10 >10 +++P-2051 +++ +++ P-2052 +++ >10 >10 +++ P-2054 +++ >10 >10 +++ P-2056+++ >10 >10 +++ P-2057 +++ >10 >10 +++ P-2058 +++ >10 >10 +++ P-2061+++ >10 >10 +++ P-2062 +++ >10 >10 +++ P-2063 +++ >10 >10 +++ P-2064+++ >10 >10 +++ P-2065 +++ >10 >10 +++ P-2066 +++ >10 >10 +++ P-2067+++ >10 >10 +++ P-2068 +++ >10 >10 +++ P-2069 +++ >10 >10 +++ P-2070+++ >10 >10 +++ P-2071 +++ >10 >10 +++ P-2072 +++ >10 >10 +++ P-2073+++ >10 >10 +++ P-2074 +++ >10 >10 +++ P-2075 +++ >10 >10 +++ P-2076+++ >10 >10 +++ P-2077 +++ >10 +++ P-2078 +++ >10 >10 +++ P-2079+++ >10 >10 +++ P-2080 +++ >10 >10 +++ P-2081 +++ >10 >10 +++ P-2082+++ >10 >10 +++ P-2083 +++ >10 >10 +++ P-2084 +++ >10 >10 +++ P-2085++ >10 >10 +++ P-2086 +++ >10 >10 +++ P-2087 +++ >10 >10 ++ P-2088+++ >10 >10 +++ P-2089 +++ >1 >1 +++ P-2090 +++ >10 >10 +++ P-2091+++ >10 >10 +++ P-2092 +++ >10 >10 +++ P-2093 +++ >1 >1 +++ P-2094+++ >10 >10 +++ P-2095 >10 >10 +++ P-2096 +++ >10 >10 + P-2097++ >10 >10 + P-2098 +++ >10 >10 +++ P-2099 +++ >10 >10 +++ P-2100+++ >10 >10 +++ P-2101 +++ >10 >10 +++ P-2102 +++ >10 >10 ++ P-2103+++ >10 >10 +++ P-2104 +++ >10 >10 +++ P-2105 +++ >10 >10 +++ P-2106+++ >10 >10 +++ P-2107 +++ >10 >10 ++ P-2108 +++ >10 >10 +++ P-2109+++ >10 >10 ++ P-2110 +++ >10 >10 +++ P-2111 +++ >10 >10 +++ P-2112+++ >10 +++ P-2113 +++ >10 >10 +++ P-2115 +++ >10 >10 +++ P-2116+++ >10 >10 +++ P-2117 +++ >10 >10 +++ P-2118 +++ >10 >10 +++ P-2119+++ >10 >10 +++ P-2120 +++ >10 >10 ++ P-2121 +++ >10 >10 +++ P-2122+++ >10 >10 +++ P-2123 +++ >10 >10 +++ P-2124 +++ >1 >10 +++ P-2125+++ >1 >10 +++ P-2126 +++ >10 +++ P-2127 +++ >10 >10 + P-2129 +++ ++++++ +++ P-2130 +++ +++ +++ +++ P-2138 +++ >10 +++ P-2152 +++ +++ +++P-2153 +++ +++ +++ +++ P-2160 +++ +++ +++ P-2161 +++ >10 +++ +++ P-2163++ >10 >10 ++ P-2164 +++ >10 +++ P-2165 +++ >10 >10 +++ P-2166 +++ >10+++ +++ P-2169 +++ +++ +++ +++ P-2170 +++ +++ +++ +++ P-2171 +++ >1 >10+++ P-2172 +++ >10 >1 +++ P-2173 +++ >1 >10 +++ P-2174 +++ >10 >10 +++P-2175 +++ >10 +++ P-2176 +++ >10 >10 +++ P-2177 +++ >10 >10 +++ P-2178+++ >10 >10 ++ P-2179 ++ >10 >10 + P-2180 +++ >10 >10 ++++ P-2181 ++++++ >10 +++ P-2182 +++ >10 >10 P-2183 +++ >10 >10Biochemical Assays and Kinome Selectivity Profiling.

As described herein, compound A is a compound of formula (I). Forexample, compound A is a compound set forth in Tables 1 and 2.

The in vitro RAF kinase activities were determined by measuringphosphorylation of a biotinylated substrate peptide as describedpreviously (Tsai, J. et al. Proc Natl Acad Sci USA 105, 3041-3046(2008)). Compounds of formula (I), e.g., compound A, was also testedagainst a panel of 287 kinases at concentrations of 1 μM in duplicate.Kinases inhibited by over 50% were followed up by IC₅₀ determination.The 287 kinases represent all major branches of the kinome phylogenetictree. The inhibition screen of 287 kinases was carried out undercontract as complementary panels at Invitrogen (Life Technologies, WI,USA) SelectScreen™ profiling service, DiscoverX (CA, USA) KINOMEScan™service, and Reaction Biology Corporation (PA, USA) Kinase HotSpot™service.

Cell Culture, pERK Assay, Growth Inhibition Assay, and PhototoxicityAssay

The B9 cell line was a gift from Allan Balmain (University ofCalifornia, San Francisco, Calif., USA). The IPC-298 cell line waspurchased from DSMZ (Braunschweig, Germany). The SK-MEL-239 andKS-MEL-239 cell lines were kindly provided by Neal Rosen (MemorialSloan-Kettering Cancer Center, New York, N.Y., USA). All other celllines were purchased from ATCC.

Phospho-ERK AlphaScreen® assay. To determine the effects of compoundtreatment upon phosphorylation of ERK1/2, cells were plated in a 96-welldish and treated with an 8-point titration of compound for one hour at37° C. before lysis. To detect pERK, cell lysates were incubated withstreptavidin-coated AlphaScreen® donor beads, anti-mouse IgGAlphaScreen® acceptor beads, a biotinylated anti-ERK1/2 rabbit antibody,and a mouse antibody that recognizes ERK1/2 only when it isphosphorylated on Thr202 and Tyr204. The biotinylated ERK1/2 antibodybinds to both the streptavidin-coated AlphaScreen® donor beads and toERK1/2 (regardless of its phosphorylation state), and the phospho-ERK1/2antibody binds to the acceptor beads and to ERK1/2 that isphosphorylated at Thr202/Tyr204. An increase in ERK1/2 phosphorylationat Thr202/Tyr204 brings the donor and acceptor AlphaScreen® beads intoclose proximity, generating a signal that can be quantified on anEnVision reader (Perkin Elmer).

Phospho-ERK immunoblot analysis. Western blots were performed bystandard techniques and analyzed on an Odyssey Infrared Scanner (Li-CORBiosciences). The following antibodies were used: pERK1/2 (T202/Y204)and ERK1/2 (Cell Signaling).

Growth inhibition assay. Cells were plated into a 96-well plate at adensity of 3000 cells per well and allowed to adhere overnight.Compounds were dissolved in DMSO, diluted 3-fold to create an 8-pointtitration, and added to cells. After a 72 h incubation, cell viabilitywas examined using CellTiter-Glo® (Promega). Data presented representthe average of at least three independent experiments.

Anchorage-independent growth assay. 2.5×10⁴ B9 cells were plated in eachwell of a six-well plate with a bottom layer of 1% and a top layer of0.4% low melting agar (Sigma A4018, Dallas, Tex.) containing RPMI1640medium with 10% FBS. For RAF inhibitor study, B9 cells grown in softagar were treated with vemurafenib, compound P-1000 or compound A atindicated concentration or dimethyl sulfoxide (DMSO) for 3 weeks. ForEGFR ligand study, B9 cells grown in soft agar were treated with AREG(R&D systems 989-AR, Minneapolis, Minn.), TGFα (R&D systems 239-A,Minneapolis, Minn.) or HB-EGF (R&D systems 259-HE, Minneapolis, Minn.)at the indicated concentrations for 3 weeks. For vemurafenib anderlotinib combination study, B9 cells grown in soft agar were treatedwith vemurafenib, erlotinib or a combination of the two compounds at theindicated concentrations or DMSO for 3 weeks. Anchorage-independentcolonies ≧100 μm were scored using AxioVision Rel 4.8 software(CarlZeiss, Wake Forest, N.C.).

B9 cells grown in soft agar were treated with AREG, TGFα or HBEGF at theindicated concentrations for 3 weeks. Anchorage-independent colonies≧100 μm were scored. B9 cells grown in soft agar were treated withvemurafenib or a combination of vemurafenib and erlotinib at theindicated concentrations for 3 weeks. Anchorage-independent colonies≧100 μm were scored.

Phototoxicity assay. The NIH 3T3 phototoxicity assay was developed basedon Organization for Economic Co-operation and Development testguidelines No. 432 (OECD Guidelines for the Testing of Chemicals/TestNo. 432: In Vitro 3T3 NRU Phototoxicity Test, 2004) with minormodifications. Two collagen-coated 96-well plates with 10⁴ NIH 3T3 cellsper well in DMEM with 10% calf serum were pre-incubated with eightdifferent concentrations of the test chemical for 1 hour. Thereafter oneof the two plates (+UV) is exposed to the non-cytotoxic UVA irradiationdose (1.7 mW/cm2=5 J/cm2) through the lid for 50 minutes whereas theother plate is kept in the dark. Cytotoxicity in this test is expressedas a concentration-dependent reduction of the uptake of the Vital dyeNeutral Red (NR) when measured 24 hours after treatment with the testchemical and irradiation. To predict the phototoxic potential, theconcentration responses obtained in the presence and in the absence ofirradiation are compared at the IC₅₀ level, i.e., the concentrationreducing cell viability to 50% compared to the untreated controls.

Microarray Gene Expression Analysis

B9 cells were plated in DMSO control or 1 μM of vemurafenib or compoundA and incubated for 16 hours. Cells were harvested, total RNA wasisolated (RNeasy Mini Kit, Qiagen), and gene expression was measuredusing Affymetrix Mouse420_2 chips (Santa Clara, Calif.) following themanufacturer's instructions. Vemurafenib response genes were identifiedby requiring the ratio between the treated and vehicle control samplesbe more than 1.9 (upregulated) or less than 0.54 (downregulated).

Western Blot (EGFR Ligand Assay)

2×10⁴ B9 cells were plated in each well of a 96-well plate and treatedwith DMSO control or compounds at indicated concentration for 48 hours.Cell supernatants were collected and cells were lysed using 1× celllysis buffer (CST 9803, Beverly, Mass.). The amount of AREG, TGFα andHB-EGF in cell supernatants or cell lysates were determined with the useof ELISA Development kits (R&D systems DY989, DY239 and 259-HE-050,Minneapolis, Minn.) according to the manufacturer's instructions.

RAF Dimerization Assays

Immunoprecipitation-Western blot assay. Cells were plated on 15-cmdishes and allowed to adhere overnight at 37° C. Cells were treated withcompound or DMSO for one hour at 37° C. prior to lysis in RIPA buffercontaining protease and phosphatase inhibitors. The lysates wereclarified by centrifugation and equal amounts were immunoprecipitatedwith antibodies for either BRAF (Santa Cruz) or CRAF (BD Biosciences)overnight at 4° C. The immunoprecipitated complexes were separated bySDS-PAGE and transferred to PVDF. Western blots were performed with BRAFand CRAF antibodies, as noted, and were visualized on a LI-COR Odysseyimaging system.

AlphaScreen assay using recombinant kinase domains. Recombinant humanBraf protein with N-terminal GST-Tag and C-terminal His-tag(GST-BRAF-His, residues 432-727), recombinant human RAF1 protein withN-terminal His-tag (His-RAF1, residues 325-648) or recombinant humanRAF1 protein with N-terminal GST tag and C-terminal His-tag(GST-RAF1-His, residues 325-648) were expressed in Sf9 insect cells viaa baculovirus expression system as previously described (Ref). His-RAF1protein was in vitro biotinylated. BRAF-RAF1 and RAF1-RAF1 interactionwas measured quantitatively using Alpha technology.

Tumor Xenograft Studies

All animal studies were conducted in accordance with the Institute forLaboratory Animal Research Guide for the Care and Use of LaboratoryAnimals and the USDA Animal Welfare Act. The same formulation was usedfor both COLO205 and B9 xenograft studies. The powder of test compoundwas dissolved in pure N-methyl-2-pyrrolidone (NMP). Diluent consists ofPEG400: TPGS:Poloxamer 407:Water (40:5:5:50). Before gavageadministration, fresh stock of NMP compound solution (or NMP forvehicle) was thoroughly mixed with the diluents to make a uniformsuspension. Dosing volume is 5 μl/g. On the last day of the efficacystudy, blood samples were collected at 0, 2, 4, and 8 hrs after lastdosing, 2 animals/time point, for PK analysis.

COLO205 tumor cells were cultured in Dulbecco's Modified Eagle's Mediumsupplemented with 10% FBS, bovine insulin, 100 U/ml penicillin and 100g/ml streptomycin at 37° C. BALB/C nude mice, female, 6-8 weeks old,weighing approximately 18-22 g, were inoculated subcutaneously at theright flank with COLO205 tumor cells (5×10⁶) in 0.1 ml of PBS mixed withmatrigel (50:50) for tumor development. The treatment was started whenmean tumor size reached approximately 100 mm³, with eight mice in eachtreatment group randomized to balance the average weight and tumor size.Thereafter tumor sizes were measured twice weekly.

B9 cells were expanded in DMEM 10% FBS 1% Penicillin/Streptomycin. Upontrypsinization the cells were washed three times with 20 ml RPMI andafter the final centrifugation re-suspended, counted and adjusted byvolume to a final concentration of 5×10⁷ cells/mL. B9 xenografts werestarted by injection of 5×10⁶ cells subcutaneously in 6-7 week oldfemale nude BALB/c mice Animals were fed a standard rodent diet andwater was supplied ad libitum. Tumor measurements were taken with anelectronic microcaliper three times weekly. Also body weights wererecorded at these times. Compound dosing started when the average sizeof tumors reached 50-70 mm³. Animals were equally distributed overtreatment groups (n=10) to balance the average tumor size Animals weredosed orally for day 1-14 twice daily and day 15-28 once daily withvehicle, vemurafenib 50 mg/kg or Compound A 50 mg/kg. TPA was put twicea week on the skin of all mice during weeks 3 and 4 at a dose of 2 μg in200 μl acetone.

Crystallization and Structure Determination

Expression and purification of BRAF and BRAF^(V600E) were carried out aspreviously described (Tsai, J. et al. Proc Natl Acad Sci USA 105,3041-3046 (2008)). Crystallization drops were prepared by mixing theprotein solution with 1 mM of compound and the same amount of reservoir,and drops were incubated by vapor diffusion (sitting drops) at 4° C. Themother liquor used to obtain co-crystals of compound A, dabrafenib andcompound P-0352 with BRAF^(V600E) consists of 0.1 M BisTris at pH 6.0,12.5% 2,5-hexabediol, 12% PEG3350. All co-crystals were flash-frozenwith liquid nitrogen, but BRAF^(V600E) co-crystals were soaked in asolution containing the mother liquor plus 20% glycerol, prior toflash-freezing. X-ray diffraction data were collected at beamline 8.3.1at the Advanced Light Source (Lawrence Berkeley Laboratory, CA, USA) andbeamline 9.1 at Stanford Synchrotron Radiation Lightsource (StanfordUniversity, CA USA). Data were processed and scaled using MOSFLM(Powell, H. R. Acta Crystallogr D Biol Crystallogr 55, 1690-1695 (1999))and SCALA in the CCP4 package (Winn, M. D. et al. Acta Crystallogr DBiol Crystallogr 67, 235-242 (2011)). All co-structures were solvedusing molecular replacement with the program MOLREP (Vagin, A. et al.Acta Crystallogr D Biol Crystallogr 66, 22-25 (2010)). The startingmodels used for are the inhibitor bound BRAF^(V600E) and BRAF^(WT),respectively (Protein Data Bank accession codes 4FK3, 1UWJ). The finalmodels were obtained after several rounds of manual rebuilding andrefinement with PHENIX (Adams, P. D. et al. Acta Crystallogr D BiolCrystallogr 66, 213-221 (2010)) and REFMAC (Murshudov, G. N. et al. ActaCrystallogr D Biol Crystallogr 53, 240-255 (1997)). A summary of thecrystallography statistics is included in Table 5.

TABLE 3 Kinase inhibitory activity of compound A versus a panel ofkinases^(a) (% inhibition at single concentration at 1 μM and IC₅₀) %Inhibi- IC₅₀ Clan Family Kinase tion (μM) TK SRC/Other PTK6_(Brk) 98.50.061 TK SRC/Other SRMS_(Srm) 98.5 <0.039 TKL RIPK-LRRK RIPK2 96.4 0.023TK SRC/Fyn FGR 94 <0.039 TKL RIPK-LRRK RIKP3 86 ND TK SRC/Fyn YES1 830.0495 TKL RAF BRAF 83 0.14 TKL MLK-ZAK ZAK 81 0.062 TK SRC/Lyn LCK 80.50.036 TKL RAF RAF1_(CRAF) 80 0.091 TK SRC/Fyn SRC_N1 78.5 0.052 STEMAP4K/ MAP4K5_(KHS1) 69.5 0.41 GCK-MST TK SRC/Lyn BLK 68 0.32 TK CSK CSK67 0.14 TKL LIMK-TESK LIMK1 65 0.24 TK SRC/Lyn LYN_B 64.5 0.16 TKEGFR/ACK ACK1 64 0.26 TK SRC/Lyn LYN_A 64 0.12 Atypical PI3K PIK3CD/60.5 0.34 PIK3R1_(p110d/p85a) Atypical PI4K PI4KB_(PI4K_beta) 60 1.1 TKSRC/Fyn FYN 57.5 0.18 TKL TGFBR TGFBR1_(ALK5) 57.5 0.36 TKL RIPK-LRRKRIPK5 57 ND Atypical PI3K PIK3C2A_(PI3KC2a) 53.5 0.41 Atypical PI3KPIK3C2B_(PI3KC2b) 52.5 0.59 ^(a)Lists of kinases minimally affected bycompound A is included below.Kinases with <50% Inhibition at 1 μM Compound aSRC, FRK_PTK5), WNK2, ACVR2B, HCK, MAP3K8_(COT), LIMK2, PDGFRA,AMPK_A2/B1/G1, CLK4, PRKCN_(PKD3), CHEK1_(CHK1), ACVR1_(ALK2)Kinases with <20% Inhibition at 1 μM Compound aMET, BMPR1A_(ALK3), CAMK2A_(CaMKII_alpha), MAP4K2_(GCK), DNA-PK,ABL2_(Arg), KDR_(VEGFR2), CDK8/cyclinC, GSK3A, EPHA5, RIPK4,PRKCB1_(PKCbeta_I), PRKC_(PKC_alpha), MARK2, PRKCQ_(PKC_theta),PIK3CA/PIK3R1_(p110a/p85a), CLK2, ABL1, EPHB2, RET, SPHK2, EPHA8,FES_(FPS), PKN1_(PRK1), CDC42_BPB_(MRCKB), SNF1LK2, NEK1,PAK7_(KIAA1264), BMX, MARK1_(MARK), NUAK1_(ARK5), CLK3, MAPK9_(JNK2),AURKB_Aurora_B), MATK_(HYL), ERBB4_(HER4), EPHA1, PRKG1,CSNK1G2_(CK1_gamma_2), HIPK4, AXL, FLT3, TEK_(Tie2), BRSK1_(SAD1),STK16, PAK3, MUSK, PHKG1, MYLK2_(skMLCK), MAPKAPK3, CDK9/CyclinT1, SLK,TAOK2_(TAO1), IGF1R, SGK_SGK1), PRKCB2_(PKCbetaII), CDK7/CyclinH/MNAT1,MAPK8_(JNK1), MAPK12_(p38_gamma), MAPK13_(p38_delta), PLK1, TTK,STK4_(MST1), IRAK1, RIPK1Kinases with <20% Inhibition at 1 μM Compound aGRK4, PRKCI_(PKC_iota), CAMK2B_(CaMKIIbeta), CAMK2Q(CaMKII_delta),DYRK3, MAP2K2_(MEK2), PAK1, EPHB1, INSRR_(IRR), NTRK3_(TRKC),PDGFRB_(PDGFRbeta), AKT2_(PKBb), SGKL_(SGK3), CAMK4_(CaMKIV), GSK3B,MERTK_(cMER), FGFR1, CAMK1D_(CaMKI_delta), PRKD1_(PKC_mu), CDK2/CyclinA,SRPK1, MAPK11_(p38_beta), NEK2, NEK4, FER, FLT4_(VEGFR3), IRAK4,AKT3_(PKBg), SGK2, ADRBK1_(GRK2), RPS6KA3_(RSK2), PRKD2_(PKD2), SRPK2,STK23_(MSSK1), DYRK1A, AURKC_(Aurora_C), PIM1, MINK1, ERBB2_(HER2),PTK2_(FAK), CSF1R_(FMS), DMPK, CSNK2A1_(CK2_alpha_1),CSNK2A2_(CK2_alpha_2), PTK2B_(PYK2), FGFR2, FLT1_(VEGFR1), PRKG2_(PKG2),PRKCD_(PKC_delta), PRKCG_(PKC_gamma), RPS6KA5_(MSK1), CDK1/CyclinB,HIPK2, AURKA_(Aurora_A), TBK1, NEK6, MAP2K1_(MEK1), MAP3K2_(MEKK2), ITK,EPHA7, LTK_(TYK1), INSR, NTRK2_(TRKB), KIT, PRKCH_(PKCeta),STK25_(YSK1), MAP4K4_(HGK), EPHA3, ROS1, MAP3K10_(MLK2), RPS6KA4_(MSK2),EEF2K, CHEK2_(CHK2), DAPK3_(ZIPK), MAPK1_(ERK2), NEK9,MAP3K7_(TAK1-TAB1), BTK, JAK2_(H1_JH2, FGFR3, MELK, PRKCZ_(PKC_zeta),RPS6KA2_(RSK3), CSNK1A 1_(CK1_alpha_1), MAPK14_(p38_alpha), TXK, EPHB3,JAK1, FGFR4, AKT1_(PKBa), AMPK_A1/B1/G1, CSNK1G1_(CK1_gamma_1),CDK9/cyclinK, PAK2_(PAK65), EPHB4, DDR1, MST1R_(RON), MAPK3_(ERK1),PIK3C3_(hVPS34), CSNK1E_(CK1_epsilon), DYRK1B, MST4, LRRK2,RPS6KA1_(RSK1), MARK3, CLK1, HIPK3_(YAK1), PRKX, PHKG2, MKNK2_(MNK2),STK33, CDK5_p35, CHUK_(IKKa), EPHA2, EPHA4, GRK7, ROCK2, DCAMKL2_(DCK2),MKNK1_(MNK1), NEK7, PLK2, MAP2K3_(MEK3), TYRO3_(RSE), JAK2, JAK3,PRKCE_(PKC_epsilon), RPS6KA6_(RSK4), PIK3CG_(p110g), MAPKAPK5_(PRAK),CDK5_p25, MAPK10_(JNK3), CAMKK1, IKBKE_(IKK_epsilon), PASK, SYK,MAPKAPK2, GSG2_(Haspin), PAK4, MAP3K9_(MLK1), RPS6KB1_(p70S6K),STK17A_(DRAK1), PAK6, TEC, ZAP70, ADRBK2_(GRK3), PRKACA_(PKA), DAPK1,MLCK_(MLCK2), MYLK_(MLCK), CSNK1D_(CK1_delta), HIPK1_(Myak),MAP3K3_(MEKK3), MAP3K14_(NIK), TAOK3_(JIK), EGFR_(ErbB1), DDR2,MAP3K11_(MLK3), ROCK1, FRAP1_(mTOR), MARK4, STK22B_(TSSK2),STK22D_(TSSK1), CSNK1G3_(CK1_gamma_3), PDK1, DYRK4, CAMKK2,CDC42_BPA_(MRCKA), NLK, PLK3, WEE1, STK3_(MST2), MAP3K5_(ASK1),IKBKB_(IKK_beta), PI4KA_(PI4K_alpha), PIM2, TYK2, GRK6, STK24_(MST3),GRK5, MAP2K6_(MKK6), NTRK1_(TRKA), SPHK1, ACVR1B_(ALK4), CAMK1

TABLE 4 Affymetrix Mouse gene probes that respond to vemurafenib and/orCompound A treatments. Vemurafenib Compound A Repl. Repl. Repl. Repl.Probe Set ID 1 2 1 2 Gene Symbol Gene Title 1426181_a_at 5.52 4.76 1.351.11 I124 interleukin 24 1416325_at 5.15 4.39 1.05 1.27 Crisp1cysteine-rich secretory protein 1 1449367_at 4.45 4.68 1.35 0.99 Trex2three prime repair exonuclease 2 1450241_a_at 4.78 4.27 1.44 1.44 Evi2aecotropic viral integration site 2a 1450791_at 4.55 4.39 1.30 1.31 Nppbnatriuretic peptide precursor type B 1417065_at 4.13 4.50 1.82 1.33 Egr1early growth response 1 1424090_at 4.08 4.46 1.22 1.35 Sdcbp2 syndecanbinding protein (syntenin) 2 1437199_at 4.17 4.31 1.39 1.25 — —1421134_at 4.28 4.16 1.65 1.47 Areg amphiregulin 1421679_a_at 4.27 4.131.42 1.36 Cdkn1a cyclin-dependent kinase inhibitor 1A (P21) 1453345_at3.86 3.92 1.15 1.20 Nipal1 NIPA-like domain containing 1 1435331_at 3.913.71 1.22 1.11 Pyhin1 pyrin and HIN domain family, member 1 1457666_s_at3.60 3.89 0.99 1.06 Ifi202b interferon activated gene 202B 1453055_at3.32 4.08 1.52 2.15 Sema6d sema domain, transmembrane domain (TM), andcytoplasmic domain, (semaphorin) 6D 1420450_at 3.42 3.93 1.25 1.31 Mmp10matrix metallopeptidase 10 1419816_s_at 3.87 3.39 1.48 1.29 Errfi1 ERBBreceptor feedback inhibitor 1 1449545_at 3.88 3.38 0.79 0.81 Fgfl8fibroblast growth factor 18 1421551_s_at 3.58 3.42 1.09 0.99 Ifi202binterferon activated gene 202B 1436584_at 3.28 3.54 1.75 1.82 Spry2sprouty homolog 2 (Drosophila) 1423690_s_at 3.37 3.20 1.11 1.22 Gpsm1G-protein signalling modulator 1 (AGS3-like, C. elegans) 1422273_at 3.303.17 1.52 1.35 Mmp1b matrix metallopeptidase 1b (interstitialcollagenase) 1448978_at 3.21 3.24 1.25 1.28 Ngef neuronal guaninenucleotide exchange factor 1416129_at 3.31 3.11 1.36 1.26 Errfi1 ERBBreceptor feedback inhibitor 1 1456321_at 3.42 2.99 1.25 1.46 Nipal1NIPA-like domain containing 1 1440559_at 3.39 2.95 1.36 1.32 Hmga2-ps1high mobility group AT-hook 2, pseudogene 1 1420352_at 3.07 3.13 1.241.12 Prss22 protease, serine, 22 1426037_a_at 3.19 2.93 1.22 1.05 Rgs16regulator of G-protein signaling 16 1439878_at 3.09 2.90 1.25 1.40 Ivlinvolucrin 1418349_at 3.29 2.70 1.23 1.16 Hbegf heparin-binding EGF-likegrowth factor 1417130_s_at 3.10 2.79 1.29 1.26 Angptl4 angiopoietin-like4 1451798_at 3.05 2.76 1.33 1.16 Il1rn interleukin 1 receptor antagonist1448562_at 2.68 2.99 1.42 1.28 Upp1 uridine phosphorylase 1 1450430_at2.66 2.97 0.87 1.09 Mrc1 mannose receptor, C type 1 1429700_at 3.18 2.471.29 0.96 3110040M04Rik RIKEN cDNA 3110040M04 gene 1436329_at 2.75 2.771.14 1.33 Egr3 early growth response 3 1416401_at 2.87 2.64 1.39 1.12Cd82 CD82 antigen 1450501_at 3.02 2.48 1.13 1.37 Itga2 integrin alpha 21449038_at 2.96 2.51 1.06 1.43 Hsd11b1 hydroxysteroid 11-betadehydrogenase 1 1455104_at 2.60 2.85 0.93 1.38 Mxd1 MAX dimerizationprotein 1 1449965_at 2.83 2.61 1.23 1.37 Mcpt8 mast cell protease 81424638_at 2.76 2.67 1.02 1.27 Cdkn1a cyclin-dependent kinase inhibitor1A (P21) 1419529_at 2.84 2.53 1.45 1.28 Il23a interleukin 23, alphasubunit p19 1448532_at 2.70 2.67 1.02 1.20 Prl8a9 prolactin family8,subfamily a, member 9 1450276_a_at 2.73 2.63 1.14 1.25 Scin scinderin1427364_a_at 2.73 2.62 1.33 1.19 Odc1 ornithine decarboxylase,structural 1 1421668_x_at 2.74 2.60 1.17 1.40 Speer3 spermatogenesisassociated glutamate (E)-rich protein 3 1449133_at 2.53 2.78 0.89 0.73Sprr1a small proline-rich protein 1A 1460521_a_at 3.03 2.32 1.30 1.34Obfc2a oligonucleotide/oligosaccharide- binding fold containing 2A1424383_at 2.58 2.69 1.62 1.45 Tmem51 transmembrane protein 511422139_at 2.45 2.82 1.02 1.28 Plau plasminogen activator, urokinase1449268_at 2.82 2.36 1.06 1.21 Gfpt1 glutamine fructose-6-phosphatetransaminase 1 1419317_x_at 2.53 2.58 0.99 0.76 Lce3c late cornifiedenvelope 3C 1418350_at 2.66 2.46 1.39 1.30 Hbegf heparin-bindingEGF-like growth factor 1428114_at 2.61 2.47 1.12 0.90 Slc14a1 solutecarrier family 14 (urea transporter), member 1 1427527_a_at 2.73 2.371.01 0.84 Pthlh parathyroid hormone-like peptide 1427512_a_at 2.61 2.471.12 1.09 Lama3 laminin, alpha 3 1419322_at 2.60 2.45 1.17 1.12 Fgd6FYVE, RhoGEF and PH domain containing 6 1419188_s_at 2.62 2.36 1.02 0.81Ccl27a/// chemokine (C-C motif) ligand Gm13306 27A///predicted gene13306 1417812_a_at 2.60 2.38 1.10 1.16 Lamb3 laminin, beta 3 1431688_at2.56 2.41 1.18 0.95 LOC73899 hypothetical LOC73899 1420537_at 2.36 2.581.35 1.22 Kctd4 potassium channel tetramerisation domain containing 41425452_s_at 2.41 2.53 1.32 1.55 Fam84a family with sequence similarity84, member A 1422138_at 2.73 2.19 1.10 1.06 Plau plasminogen activator,urokinase 1424306_at 2.51 2.35 1.04 1.09 Elovl4 elongation of very longchain fatty acids (FEN1/Elo2, SUR4/Elo3, yeast)-like 4 1434109_at 2.502.33 1.14 1.01 Sh3bgrl2 SH3 domain binding glutamic acid-rich proteinlike 2 1436659_at 2.44 2.37 1.33 1.42 Dclk1 doublecortin-like kinase 11426300_at 2.35 2.44 1.39 1.59 Alcam activated leukocyte cell adhesionmolecule 1422222_at 2.50 2.27 1.43 1.15 Ivl involucrin 1435330_at 2.342.38 1.18 1.16 Pyhin1 pyrin and HIN domain family, member 1 1450262_at2.62 2.12 1.47 1.19 Clcf1 cardiotrophin-like cytokine factor 11451308_at 2.50 2.21 1.04 1.01 Elovl4 elongation of very long chainfatty acids (FEN1/Elo2, SUR4/Elo3, yeast)-like 4 1450976_at 2.23 2.471.06 1.29 Ndrg1 N-myc downstream regulated gene 1 1456248_at 2.26 2.451.40 1.21 Lce3f/// late cornified envelope 3F/// LOC630971 hypotheticalprotein LOC630971 1452352_at 2.37 2.30 1.28 1.08 Ctla2b cytotoxic Tlymphocyte- associated protein 2 beta 1423635_at 2.41 2.23 1.31 1.40Bmp2 bone morphogenetic protein 2 1441315_s_at 2.46 2.18 1.12 1.10Slc19a2 solute carrier family 19 (thiamine transporter), member 21423017_a_at 2.63 2.03 1.13 1.04 Il1rn interleukin 1 receptor antagonist1421269_at 2.46 2.16 1.33 1.05 Ugcg UDP-glucose ceramideglucosyltransferase 1417677_at 2.18 2.39 1.37 1.37 Opn3 opsin 31437486_at 2.49 2.08 1.10 1.50 Gprc5a G protein-coupled receptor, familyC, group 5, member A 1454254_s_at 2.37 2.18 1.18 1.06 1600029D21RikRIKEN cDNA 1600029D21 gene 1430700_a_at 2.36 2.18 1.38 1.10 Pla2g7phospholipase A2, group VII (platelet-activating factor acetylhydrolase,plasma) 1416488_at 2.23 2.31 1.29 1.18 Ccng2 cyclin G2 1452087_at 2.202.32 1.27 1.19 Epsti1 epithelial stromal interaction 1 (breast)1420407_at 2.29 2.24 1.36 1.13 Ltb4r1 leukotriene B4 receptor 11437092_at 2.37 2.13 1.26 1.14 Clip4 CAP-GLY domain containing linkerprotein family, member 4 1427885_at 2.20 2.27 1.18 1.10 Pold4 polymerase(DNA-directed), delta 4 1428195_at 2.42 2.06 1.71 1.87 Ahcyl2S-adenosylhomocysteine hydrolase-like 2 1436100_at 2.12 2.35 1.28 1.21Sh2d5 SH2 domain containing 5 1451501_a_at 2.21 2.25 1.24 1.15 Ghrgrowth hormone receptor 1431611_a_at 2.15 2.31 1.72 1.35 Cadm1 celladhesion molecule 1 1428419_at 2.16 2.28 1.02 0.78 5430411K18Rik RIKENcDNA 5430411K18 gene 1454710_at 2.39 2.03 1.29 1.07 Spink2 serinepeptidase inhibitor, Kazal type 2 1452521_a_at 2.33 2.09 1.28 1.15 Plaurplasminogen activator, urokinase receptor 1439797_at 2.09 2.32 1.23 1.02Ppard peroxisome proliferator activator receptor delta 1422324_a_at 2.112.28 1.03 0.94 Pthlh parathyroid hormone-like peptide 1434059_at 2.262.10 0.99 0.84 B230312A22Rik RIKEN cDNA B230312A22 gene 1415936_at 2.212.16 1.18 1.30 Bcar3 breast cancer anti-estrogen resistance 3 1417837_at2.26 2.11 1.33 1.08 Phlda2 pleckstrin homology-like domain, family A,member 2 1442350_at 2.22 2.13 1.01 1.13 — — 1435066_at 2.04 2.32 1.291.22 Pitpnc1 phosphatidylinositol transfer protein, cytoplasmic 11435695_a_at 2.16 2.19 1.24 1.18 Ggct gamma-glutamyl cyclotransferase1426708_at 2.19 2.15 1.21 1.16 Antxr2 anthrax toxin receptor 21426806_at 2.33 2.02 1.06 1.17 Obfc2a oligonucleotide/oligosaccharide-binding fold containing 2A 1451529_at 1.91 2.47 1.27 1.49 Sgtb smallglutamine-rich tetratricopeptide repeat (TPR)- containing, beta1421279_at 2.23 2.11 1.14 1.13 Lamc2 laminin, gamma 2 1417962_s_at 2.192.14 1.14 1.21 Ghr growth hormone receptor 1426972_at 2.06 2.26 1.011.29 Sec24d Sec24 related gene family, member D (S. cerevisiae)1448810_at 2.16 2.16 1.33 0.87 Gne glucosamine 1428228_at 2.18 2.13 1.341.16 Pgm3 phosphoglucomutase 3 1448364_at 2.30 2.01 1.41 1.38 Ccng2cyclin G2 1428851_at 2.30 2.01 1.21 1.11 1300014I06Rik RIKEN cDNA1300014I06 gene 1449125_at 2.14 2.10 1.24 1.00 Tnfaip8l1 tumor necrosisfactor, alpha- induced protein 8-like 1 1448617_at 2.24 1.99 1.27 1.45Cd53 CD53 antigen 1417328_at 2.20 2.01 1.19 0.99 Ercc1 excision repaircross- complementing rodent repair deficiency, complementation group 11450376_at 2.20 2.00 0.94 0.96 Mxi1 Max interacting protein 1 1433909_at2.02 2.17 0.99 1.06 Syt17 synaptotagmin XVII 1416811_s_at 2.28 1.92 1.031.02 Ctla2a/// cytotoxic T lymphocyte- Ctla2b associated protein 2alpha/// cytotoxic T lymphocyte- associated protein 2 beta 1424022_at2.27 1.92 1.18 1.09 Osgin1 oxidative stress induced growth inhibitor 11417488_at 2.09 2.05 1.30 0.93 Fosl1 fos-like antigen 1 1449408_at 2.042.08 1.22 1.11 Jam2 junction adhesion molecule 2 1441917_s_at 2.00 2.111.05 0.96 Tmem40 transmembrane protein 40 1419149_at 2.13 1.99 1.11 1.01Serpine1 serine (or cysteine) peptidase inhibitor, Glade E, member 11436917_s_at 2.22 1.89 0.86 0.78 Gpsm1 G-protein signalling modulator 1(AGS3-like, C. elegans) 1454649_at 2.02 2.08 1.29 1.36 Srd5a1 steroid 5alpha-reductase 1 1418538_at 2.08 2.02 1.11 0.97 Kdelr3 KDEL(Lys-Asp-Glu-Leu) endoplasmic reticulum protein retention receptor 31452058_a_at 2.07 2.02 1.28 1.13 Rnf11 ring finger protein 111437100_x_at 2.03 2.05 1.35 1.21 Pim3 proviral integration site 31416246_a_at 1.90 2.19 1.42 1.19 Coro1a coronin, actin binding protein1A 1417902_at 2.00 2.07 1.14 1.10 Slc19a2 solute carrier family 19(thiamine transporter), member 2 1423933_a_at 2.06 2.01 1.12 0.991600029D21Rik RIKEN cDNA 1600029D21 gene 1431422_a_at 2.14 1.93 1.080.94 Dusp14 dual specificity phosphatase 14 1417625_s_at 2.03 2.03 1.061.17 Cxcr7 chemokine (C-X-C motif) receptor 7 1456284_at 2.10 1.95 1.321.06 Tmem171 transmembrane protein 171 1424471_at 2.18 1.89 1.31 1.30Rapgef3 Rap guanine nucleotide exchange factor (GEF) 3 1426306_a_at 2.181.87 1.10 0.97 LOC100046560/// similar to melanoma antigen Maged2 familyD, 2///melanoma antigen, family D, 2 1437271_at 2.09 1.96 1.22 0.93Clcf1 cardiotrophin-like cytokine factor 1 1431416_a_at 2.12 1.93 1.141.03 Jam2 junction adhesion molecule 2 1442363_at 2.08 1.96 1.30 1.231110012J17Rik RIKEN cDNA 1110012J17 gene 1422028_a_at 2.13 1.91 1.040.96 Ets1 E26 avian leukemia oncogene 1, 5′ domain 1435460_at 2.07 1.961.37 1.28 Prkg2 protein kinase, cGMP-dependent, type II 1438038_at 2.101.93 1.19 1.06 4930402H24Rik RIKEN cDNA 4930402H24 gene 1448855_at 1.972.05 1.33 1.22 Rassf1 Ras association (RalGDS/AF-6) domain family member1 1427278_at 1.98 2.03 1.00 1.07 Clip4 CAP-GLY domain containing linkerprotein family, member 4 1431691_a_at 1.98 2.04 1.41 1.13 Rab31 RAB31,member RAS oncogene family 1421403_at 2.04 1.96 1.37 1.11 Pi15 peptidaseinhibitor 15 1448894_at 2.01 1.99 1.18 1.05 Akr1b8 aldo-keto reductasefamily 1, member B8 1425660_at 2.08 1.92 1.39 1.32 Btbd3 BTB (POZ)domain containing 3 1430623_s_at 2.11 1.88 1.00 1.05 Obfc2aoligonucleotide/oligosaccharide- binding fold containing 2A 1434601_at2.11 1.89 1.14 1.00 Amigo2 adhesion molecule with Ig like domain 21453278_a_at 2.00 1.99 1.02 1.03 Clip4 CAP-GLY domain containing linkerprotein family, member 4 1456150_at 1.99 1.99 1.24 1.27 Jhdm1d jumonji Cdomain-containing histone demethylase 1 homolog D (S. cerevisiae)1439434_x_at 2.06 1.91 0.87 1.08 Sh2d5 SH2 domain containing 51452203_at 2.07 1.90 1.20 1.23 Obfc2a oligonucleotide/oligosaccharide-binding fold containing 2A 1422101_at 2.04 1.93 0.95 0.88 Tnfrsf23 tumornecrosis factor receptor superfamily, member 23 1419722_at 2.02 1.941.17 1.21 Klk8 kallikrein related-peptidase 8 1422924_at 2.01 1.94 1.651.27 Tnfsf9 tumor necrosis factor (ligand) superfamily, member 91434252_at 1.99 1.95 1.21 1.12 Tmcc3 transmembrane and coiled coildomains 3 1420760_s_at 1.90 2.04 0.95 0.96 Ndrg1 N-myc downstreamregulated gene 1 1422240_s_at 1.95 1.98 1.04 1.11 Sprr2h smallproline-rich protein 2H 1434092_at 2.04 1.89 0.99 0.77 Atg9b ATG9autophagy related 9 homolog B (S. cerevisiae) 1415828_a_at 2.05 1.881.27 1.11 Serp1 stress-associated endoplasmic reticulum protein 11456174_x_at 1.92 2.00 0.94 0.95 Ndrgl N-myc downstream regulated gene 11460472_at 1.91 1.99 1.29 1.35 Cdk3 cyclin-dependent kinase 3 1423597_at2.02 1.88 0.94 1.11 Atp8a1 ATPase, aminophospholipid transporter (APLT),class I, type 8A, member 1 1448613_at 2.00 1.89 1.12 1.02 Ecm1extracellular matrix protein 1 1420913_at 1.92 1.96 1.05 1.07 Slco2a1solute carrier organic anion transporter family, member 2a1 1421943_at1.93 1.92 1.20 1.06 Tgfa transforming growth factor alpha 1418539_a_at1.94 1.89 1.12 1.09 Ptpre protein tyrosine phosphatase, receptor type, E1423543_at 1.88 1.95 1.09 0.90 Swap70 SWA-70 protein 1438699_at 1.891.87 1.19 1.18 Srd5a1 steroid 5 alpha-reductase 1 1446791_at 1.12 0.480.40 0.28 Pi15 peptidase inhibitor 15 1426848_at 0.69 0.75 0.51 0.49LOC100047481/// similar to SEC24 related gene Sec24b family, member B(S. cerevisiae)/// Sec24 related gene family, member B (S. cerevisiae)1421888_x_at 0.65 0.63 0.42 0.36 Aplp2 amyloid beta (A4) precursor-likeprotein 2 1440169_x_at 0.53 0.53 0.69 0.69 Ifnar2 interferon (alpha andbeta) receptor 2 1429844_at 0.52 0.53 0.90 0.82 2310043J07Rik RIKEN cDNA2310043J07 gene 1456874_at 0.52 0.54 0.83 0.91 Flrt2 fibronectin leucinerich transmembrane protein 2 1422537_a_at 0.53 0.49 1.00 0.82 Id2inhibitor of DNA binding 2 1417533_a_at 0.50 0.51 0.97 0.88 Itgb5integrin beta 5 1436944_x_at 0.53 0.48 0.69 0.80 Pisd///Pisd-phosphatidylserine decarboxylase ps1///Pisd-ps3/// phosphatidylserinedecarboxylase, pseudogene 1/// phosphatidylserine decarboxylase,pseudogene 3 1457042_at 0.48 0.52 1.03 0.96 AI256396 EST AI2563961417495_x_at 0.48 0.51 0.99 1.16 Cp ceruloplasmin 1430567_at 0.46 0.530.88 0.78 Spink5 serine peptidase inhibitor, Kazal type 5 1445758_at0.47 0.52 0.88 0.84 — — 1460302_at 0.49 0.50 0.78 0.80 Thbs1thrombospondin 1 1460695_a_at 0.51 0.48 0.92 0.80 2010111I01Rik RIKENcDNA 2010111I01 gene 1456725_x_at 0.48 0.49 0.62 0.59 Ezr ezrin1437982_x_at 0.51 0.45 0.63 0.79 Cox15 COX15 homolog, cytochrome coxidase assembly protein (yeast) 1447661_at 0.53 0.43 0.54 0.81 — —1439109_at 0.45 0.50 0.76 0.66 Ccdc68 coiled-coil domain containing 681419671_a_at 0.49 0.45 1.01 0.89 Il17rc interleukin 17 receptor C1455299_at 0.50 0.44 0.73 0.72 Vgll3 vestigial like 3 (Drosophila)1455241_at 0.44 0.50 0.78 0.91 BC037703 cDNA sequence BC0377031422771_at 0.46 0.47 0.90 0.81 Smad6 MAD homolog 6 (Drosophila)1438664_at 0.44 0.49 0.96 0.94 Prkar2b protein kinase, cAMP dependentregulatory, type II beta 1457568_at 0.44 0.50 0.83 0.79 Hnrnpdheterogeneous nuclear ribonucleoprotein D 1447845_s_at 0.46 0.46 0.750.84 Vnn1 vanin 1 1430010_at 0.43 0.49 0.89 0.72 Ncapd2 non-SMCcondensin I complex, subunit D2 1435176_a_at 0.44 0.46 0.70 0.75 Id2inhibitor of DNA binding 2 1434957_at 0.44 0.46 1.05 0.74 Cdon celladhesion molecule- related/down-regulated by oncogenes 1416527_at 0.420.48 1.03 0.97 Rab32 RAB32, member RAS oncogene family 1449297_at 0.410.47 0.89 0.94 Casp12 caspase 12 1455981_at 0.41 0.46 0.47 0.99Gm11263/// predicted gene 11263///predicted Gm12242/// gene12242///predicted gene Gm13654/// 13654///40S ribosomal proteinGm14138/// S6 (Phosphoprotein NP33)/// Gm16406/// ribosomal protein S6pseudogene/// Gm4796/// predicted gene 4796/// Gm6476/// predicted gene6476///predicted Gm9143/// gene 9143///similar to ribosomalLOC100043734/// protein S6///similar to 40S LOC236932/// ribosomalprotein S6///similar to LOC623245/// 40S ribosomal protein S6///LOC639593/// similar to 40S ribosomal protein Rps6 S6///ribosomalprotein S6 1454048_a_at 0.40 0.46 0.74 0.79 4931408A02Rik/// RIKEN cDNA4931408A02 gene/// LOC630876 similar to Protein C21orf63 homologprecursor 1454699_at 0.50 0.37 0.70 0.70 LOC100047324/// similar toSesn1 protein///sestrin Sesn1 1 1454780_at 0.42 0.44 0.95 0.74 Galntl4UDP-N-acetyl-alpha-D- galactosamine: polypeptide N-acetylgalactosaminyltransferase- like 4 1449334_at 0.43 0.42 0.80 0.82Timp3 tissue inhibitor of metalloproteinase 3 1451446_at 0.41 0.43 0.680.84 Antxr1 anthrax toxin receptor 1 1420955_at 0.38 0.47 0.88 0.83Vsnl1 visinin-like 1 1426260_a_at 0.39 0.45 1.21 1.15 Ugt1a1/// UDPglucuronosyltransferase 1 Ugt1a10/// family, polypeptide Al///UDPUgt1a2/// glycosyltransferase 1 family, Ugt1a5/// polypeptide A10///UDPUgt1a6a/// glucuronosyltransferase 1 family, Ugt1a6b/// polypeptideA2///UDP Ugt1a7c/// glucuronosyltransferase 1 family, Ugt1a9 polypeptideAS///UDP glucuronosyltransferase 1 family, polypeptide A6A///UDPglucuronosyltransferase 1 family, polypeptide A6B///UDPglucuronosyltransferase 1 family, polypeptide A7C///UDPglucuronosyltransferase 1 family, polypeptide A9 1439016_x_at 0.40 0.420.99 0.80 Sprr2a small proline-rich protein 2A 1454877_at 0.40 0.42 1.030.97 Sertad4 SERTA domain containing 4 1424783_a_at 0.39 0.43 1.03 0.95Ugt1a1/// UDP glucuronosyltransferase 1 Ugt1a10/// family, polypeptideA1///UDP Ugt1a2/// glycosyltransferase 1 family, Ugt1a5/// polypeptideA10///UDP Ugt1a6a/// glucuronosyltransferase 1 family, Ugt1a6b///polypeptide A2///UDP Ugt1a7c/// glucuronosyltransferase 1 family, Ugt1a9polypeptide AS///UDP glucuronosyltransferase 1 family, polypeptideA6A///UDP glucuronosyltransferase 1 family, polypeptide A6B///UDPglucuronosyltransferase 1 family, polypeptide A7C///UDPglucuronosyltransferase 1 family, polypeptide A9 1417494_a_at 0.39 0.430.63 0.72 Cp ceruloplasmin 1443536_at 0.39 0.40 0.49 0.76 Slc7a11 solutecarrier family 7 (cationic amino acid transporter, y + system), member11 1451006_at 0.40 0.39 0.77 0.75 Xdh xanthine dehydrogenase1460220_a_at 0.40 0.38 0.77 0.91 Csf1 colony stimulating factor 1(macrophage) 1420380_at 0.37 0.41 1.06 0.94 Ccl2 chemokine (C-C motif)ligand 2 1418497_at 0.39 0.38 0.82 0.83 Fgf13 fibroblast growth factor13 1450618_a_at 0.36 0.41 0.88 0.73 Sprr2a small proline-rich protein 2A1449815_a_at 0.38 0.38 0.95 0.89 Ssbp2 single-stranded DNA bindingprotein 2 1440147_at 0.34 0.38 0.99 0.99 Lgi2 leucine-rich repeat LGIfamily, member 2 1427747_a_at 0.36 0.35 0.84 0.82 Lcn2 lipocalin 21438931_s_at 0.35 0.33 0.53 0.80 LOC100047324/// similar to Sesnlprotein///sestrin Sesn1 1 1427183_at 0.30 0.37 0.56 0.76 Efemp1epidermal growth factor- containing fibulin-like extracellular matrixprotein 1 1448734_at 0.31 0.30 0.88 0.89 Cp ceruloplasmin 1449335_at0.24 0.36 0.73 0.70 Timp3 tissue inhibitor of metalloproteinase 31418240_at 0.30 0.28 0.75 0.81 Gbp2 guanylate binding protein 21419089_at 0.26 0.31 0.74 0.76 Timp3 tissue inhibitor ofmetalloproteinase 3 1438988_x_at 0.26 0.27 0.26 0.63 Hn1 hematologicaland neurological expressed sequence 1 1449227_at 0.25 0.29 0.84 0.84Ch25h cholesterol 25-hydroxylase 1435906_x_at 0.21 0.30 0.85 0.79 Gbp2guanylate binding protein 2 1416454_s_at 0.23 0.20 0.74 0.57 Acta2actin, alpha 2, smooth muscle, aorta 1460250_at 0.23 0.20 0.99 0.83Sostdc1 sclerostin domain containing 1 1449340_at 0.17 0.20 0.99 1.02Sostdc1 sclerostin domain containing 1 1416612_at 0.19 0.16 0.50 0.49Cyp1b1 cytochrome P450, family 1, subfamily b, polypeptide 1

TABLE 5 Chromosomal translocations affecting RAF genes create oncogenicBRAF fusion proteins ^(a) Fusion BRAF CRAF Protein partner ^(b) exonsexons length ^(c) Frequency Thyroid AKAP9 9-18 1473 (386) 11%radiation-induced papillary cancer carcinomas ⁷ Pilocytic KIAA159 9-182135 (386) 66% pilocytic astrocytomas ⁸ astrocytoma Pilocytic FAM131B9-18  404 (386) 2-3% (3 out of 125) ⁹ astrocytoma Prostate SLC45A3 8-18 329 (329) 1-2% (6 out of 349) ¹⁰ cancer Prostate ESRP1 6-17 1060 (454)1% (4 out of 450) ¹⁰ cancer Gastric cancer AGTRAP 8-18  597 (439) 2% (2out of 105) ¹⁰ ^(a) Fusion results in the loss of the N-terminus RASbinding domain (RBD) and expression of truncated RAF protein retainingthe entire functional kinase domain. ^(b) Gene symbols: SLC45A3, solutecarrier family 45, member 3 (also known as prostein or prostateassociated protein 6); ESRP1, epithelial splicing regulatory factor-1;AGTRAP, type-1 angiotensin II receptor associated protein; ^(c) Thenumber of amino acid in the protein encoded by the fusion gene. Thenumber of amino acid from RAF is shown in parenthesis. ⁷ Ciampi, R. etal. Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathwayactivation in thyroid cancer. J Clin Invest 115, 94-101 (2005). ⁸ Jones,D. T. et al. Tandem duplication producing a novel oncogenic BRAF fusiongene defines the majority of pilocytic astrocytomas. Cancer Res 68,8673-8677 (2008). ⁹ Cin, H. et al. Oncogenic FAM131B-BRAF fusionresulting from 7q34 deletion comprises an alternative mechanism of MAPKpathway activation in pilocytic astrocytoma. Acta Neuropathol 121,763-774 (2011). ¹⁰ Palanisamy, N. et al. Rearrangements of the RAFkinase pathway in prostate cancer, gastric cancer and melanoma. Nat Med16, 793-798 (2010).

TABLE 6 Data collection and refinement statistics BRAF^(V600E)-BRAF^(V600E)- BRAF^(V600E)- Compound A Dabrafenib P-0352 Data collectionSpace group P2₁2₁2₁ P2₁2₁2₁ P2₁2₁2₁ Cell dimensions a, b, c (Å) 50.3,104.8, 110.2 53.7, 105.7, 109.7 51.9, 105.4, 111.3 Resolution (Å)^(a)76.0-2.47 109.7-2.50 111.3-2.80 (2.47-2.58) (2.64-2.5)  (2.95-2.80)R_(sym) or R_(merge) 0.077 (0.743) 0.071 (0.531) 0.108 (0.591) I/σI 7.8(1.0) 8.1 (1.4) 5.1 (1.5) Completeness (%) 100.0 (100.0) 99.9 (99.9) 99.9 (100.0) Redundancy 5.8 (5.9) 6.1 (6.2) 4.6 (4.8) RefinementResolution (Å) 76.0-2.47  54.9-2.50 55.7-2.8 No. reflections 22,00622,263 15,592 R_(work/) R_(free) 0.234/0.273 0.212/0.244 0.258/0.296R.m.s deviations Bond lengths (Å) 0.003 0.003 0.003 Bond angles (°) 0.70.7 0.7 Most favored region (%)^(b) 95.1 96.5 94.8 Additional allowedregion 4.9 3.5 4.6 (%)^(b) Disallowed region (%)^(b) 0.0 0.0 0.7^(a)Highest resolution shell is shown in parenthesis. ^(b)In theRamachandran plot

All patents, patent applications and other references cited in thespecification are indicative of the level of skill of those skilled inthe art to which the disclosure pertains, and are incorporated byreference in their entireties, including any tables and figures, to thesame extent as if each reference had been incorporated by reference inits entirety individually.

One skilled in the art would readily appreciate that the disclosure iswell adapted to obtain the ends and advantages mentioned, as well asthose inherent therein. The methods, variances, and compositionsdescribed herein as presently representative of preferred embodimentsare exemplary and are not intended as limitations on the scope of thedisclosure. Changes therein and other uses will occur to those skilledin the art, which are encompassed within the spirit of the disclosure,are defined by the scope of the claims.

While this disclosure has been made with reference to specificembodiments, it is apparent that other embodiments and variations ofthis disclosure may be devised by others skilled in the art withoutdeparting from the true spirit and scope of the disclosure.

In addition, where features or aspects of the disclosure are describedin terms of Markush groups or other grouping of alternatives, thoseskilled in the art will recognize that the invention is also therebydescribed in terms of any individual member or subgroup of members ofthe Markush group or other group.

Also, unless indicated to the contrary, where various numerical valuesare provided for embodiments, additional embodiments are described bytaking any two different values as the endpoints of a range. Such rangesare also within the scope of the disclosure.

What is claimed is:
 1. A compound having formula (Ic-1a)

or a pharmaceutically acceptable salt, a solvate, a tautomer or astereoisomer thereof, wherein: R¹⁶ is hydrogen, optionally substitutedaryl or optionally substituted C₁₋₆alkyl; R¹⁹ is hydrogen or2-(methoxycarbonylamino)propyl; R⁴ is hydrogen, fluoro, chloro, —CH₃,—CN, or —CF₃; and R¹ and R² are each independently optionallysubstituted alkyl.
 2. The compound of claim 1, wherein R¹⁹ is hydrogen.3. The compound of claim 1, wherein R⁴ is hydrogen.
 4. A pharmaceuticalcomposition comprising a compound according to claim 1 and apharmaceutical acceptable carrier, diluent or excipient.
 5. Thepharmaceutical composition of claim 4, further comprising anothertherapeutic agent.
 6. A method for treating a subject suffering from ametastatic melanoma, a thyroid cancer, a colorectal cancer, a lungcancer or an ovarian cancer, said method comprising: administering tothe subject in need thereof an effective amount of a compound ofclaim
 1. 7. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt, a solvate, a tautomer or astereoisomer thereof.
 8. A method for treating a subject suffering froma metastatic melanoma, a thyroid cancer, a colorectal cancer, a lungcancer or an ovarian cancer, said method comprising: administering tothe subject in need thereof an effective amount of a compound of claim 7or a pharmaceutically acceptable salt, a solvate, a tautomer or astereoisomer thereof.